Methods for treating retinopathy with extended therapeutic effect

ABSTRACT

Methods for treating and preventing ocular conditions by administering an compound to the vitreous chamber of a patient at risk of, or suffering from, the ocular condition.

CROSS REFERENCE

The present application is a continuation of U.S. patent applicationSer. No. 14/306,363, filed on Jun. 17, 2014, which is a continuation ofU.S. patent application Ser. No. 13/946,294, filed on Jul. 19, 2013,which is a continuation of U.S. patent application Ser. No. 13/604,809,filed on Sep. 6, 2012, which is a continuation of U.S. patentapplication Ser. No. 11/292,544, filed Dec. 2, 2005, which is acontinuation in part of U.S. patent application Ser. No. 10/837,357,filed Apr. 30, 2004, the entire contents of all of the precedingapplications are hereby incorporated by reference.

BACKGROUND

This invention relates to methods for extended treatment of an ocularcondition. In particular the present invention releases to methods forextended treatment of an ocular condition with an intraocular implant.

An ocular condition can include an inflammatory, neoplastic, infectious,vascular, neovascular and/or degenerative disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. An anterior ocular condition is adisease, ailment or condition which affects or which involves ananterior (i.e. front of the eye) ocular region, location or site(hereafter an ocular site), such as a periocular muscle, an eye lid oran eye ball tissue or fluid which is located anterior to the posteriorwall of the lens capsule or ciliary muscles. Thus, an anterior ocularcondition primarily affects or involves, the conjunctiva, the cornea,the anterior chamber, the iris, the posterior chamber (behind the irisbut in front of the posterior wall of the lens capsule), the lens or thelens capsule and blood vessels and nerve which vascularize or innervatean anterior ocular region or site. A posterior ocular condition is adisease, ailment or condition which primarily affects or involves aposterior ocular site such as choroid or sclera (in a position posteriorto a plane through the posterior wall of the lens capsule), vitreous,vitreous chamber, retina, optic nerve (including the optic disc), andblood vessels and nerves which vascularize or innervate a posteriorocular site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, macular degeneration (such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); macular hole; light, radiation or thermal damageto a posterior ocular tissue; choroidal neovascularization; acutemacular neuroretinopathy; macular edema (such as cystoid macular edemaand diabetic macular edema); Behcet's disease, retinal disorders,diabetic retinopathy (including proliferative diabetic retinopathy);retinal arterial occlusive disease; central retinal vein occlusion;uveitic retinal disease; retinal detachment; ocular trauma which affectsa posterior ocular site; a posterior ocular condition caused by orinfluenced by an ocular laser treatment; posterior ocular conditionscaused by or influenced by a photodynamic therapy; photocoagulation;radiation retinopathy; epiretinal membrane disorders; branch retinalvein occlusion; anterior ischemic optic neuropathy; non-retinopathydiabetic retinal dysfunction, retinitis pigmentosa and glaucoma.Glaucoma can be considered a posterior ocular condition because thetherapeutic goal is to prevent the loss of or reduce the occurrence ofloss of vision due to damage to or loss of retinal cells or retinalganglion cells (i.e. neuroprotection).

An anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia;hyperopia; pupil disorders; refractive disorders and strabismus.Glaucoma can also be considered to be an anterior ocular conditionbecause a clinical goal of glaucoma treatment can be to reduce ahypertension of aqueous fluid in the anterior chamber of the eye (i.e.reduce intraocular pressure).

The present invention is directed to a method for providing an extendedtreatment of an ocular condition, such as an anterior ocular conditionor a posterior ocular condition or to an ocular condition which can becharacterized as both an anterior ocular condition and a posteriorocular condition.

Therapeutic compounds useful for the treatment of an ocular conditioncan include cytokines and active agents with, for example, ananti-neoplastic (i.e. anti-cancer), anti-angiogenesis, kinaseinhibition, anticholinergic, anti-adrenergic and/or anti-inflammatoryactivity.

Macular degeneration, such as age related macular degeneration (“AMD”)is a leading cause of irreversible vision loss in elderly populations.It is estimated that thirteen million Americans have evidence of maculardegeneration. Macular degeneration results in a break down or injury tothe macula, the central part of the retina responsible for the sharp,direct vision needed to read or drive. Central vision is especially orselectively affected. Macular degeneration is diagnosed as either dry orwet (exudative). The dry form of macular degeneration is more commonthan the wet form of macular degeneration, with about 90% of AMDpatients being diagnosed with dry AMD. The wet form of the diseaseusually leads to more rapid and more serious vision loss. Maculardegeneration can produce a slow or sudden painless loss of vision. Thecause of macular degeneration is not clear. The dry form of AMD mayresult in thinning of macular tissues, depositing of pigment in themacula, or a combination of the two processes. With wet AMD, new bloodvessels grow within and beneath the retina and leak blood and fluid.This leakage causes injury to retinal cells and creates blind spots incentral vision.

Macular edema (ME) can result in a swelling or thickening of the macularand appears to be a nonspecific response of the retina to a variety ofinsults. Thus, ME is associated with a number of diseases, includinganterior or posterior uveitis, retinal vascular abnormalities (diabeticretinopathy and retinal venous occlusive disease), as a sequela ofcataract surgery (Irvine-Gass Syndrome), macular degeneration,vitreo-macular traction syndrome, inherited or acquired retinaldegeneration, eye inflammation, idiopathic central serouschorioretinopathy, pars planitis, retinitis pigmentosa, radiationretinopathy, posterior vitreous detachment, epiretinal membraneformation, idiopathic juxtafoveal retinal telangiectasia, followingNd:YAG capsulotomy or iridotomy. Some patients with ME may have ahistory of use of topical epinephrine or prostaglandin analogs forglaucoma. Macular edema involves the development of microangiopathy,characterized by abnormal retinal vessel permeability and capillaryleakage into the adjacent retinal tissues. The macula becomes thickeneddue to accumulation of fluid which leaks out of weak blood vessel wallsdue to a breakdown of the inner blood-retinal barrier at the level ofthe capillary endothelium, often resulting in significant disturbancesin visual acuity. The blood and fluid leaks out of the weak vessel wallsinto a very small area of the macula which is rich in cones, thephotoreceptors that detect color and from which daytime vision depends.Blurring then occurs in the middle or just to the side of the centralvisual field. Visual loss can progress over a period of years. Symptomsof ME include blurred central vision, distorted vision, vision tintedpink and light sensitivity.

In some cases macular edema can resolves spontaneously or with showremission after a short-term treatment. However, in cases of persistentmacular edema (PME), visual loss continues to be a significanttherapeutic challenge. Therapies for macular edema utilize a stepwiseapproach including surgical and medical methods. A first line oftreatment for certain types of ME can be anti-inflammatory dropstopically applied. Currently there are no approved therapies for thetreatment of PME. Macular edema that has failed to respond to drugtherapy and laser photocoagulation represents a significant unmetmedical need.

Drug therapy for macular edema can include topical, periocular,subconjunctival/intravitreal, or systemic corticosteroids; topical andsystemic nonsteroidal anti-inflammatory agents (NSAIDs); and/orimmunosuppressants. Nonetheless, with variable incidence, macular edemacan persist regardless of treatment or causation resulting in severevision loss. Liquid, intravitreal triamcinolone acetonide (availablefrom Bristol Myers Squibb under the tradename Kenalog-40®) injection hasbeen used to treat ocular inflammation and macula edema. Kenalog-40® isa suspension triamcinolone acetonide (40 mg/mL) formulated with sodiumchloride for isotonicity, 0.9% (w/v) benzyl alcohol as preservative,0.75% carboxymethylcellulose sodium, and 0.04%, polysorbate 80. It isapproved for intramuscular depot delivery for the treatment ofinflammation and has been used intravitreally to treat ocularinflammation as well as macular edema due to numerous causes.Unfortunately, side-effects including elevated intraocular pressure,cataract, endophthalmitis (such as infectious endophthalmitis andsterile endophthalmitis), retinal toxicity and crystalline retinaldeposits have been reported from clinical use of intravitrealtriamcinolone acetonide.

Surgical methods for the treatment of macular edema including laserphotocoagulation have had mixed results. Focal/grid laserphotocoagulation for the prevention of moderate visual loss has beenshown to be efficacious in diabetic retinopathy and branch retinal veinocclusion patients, but not in central retinal vein occlusion patients.As a last resort, a vitrectomy is sometimes performed in patients whohave persistent macular edema that has failed to respond to lessinvasive treatments.

Dexamethasone, a potent anti-inflammatory in the corticosteroid family,has been shown to suppress inflammation by inhibiting edema, fibrindeposition, capillary deposition and phagocytic migration of theinflammatory response. Corticosteroids prevent the release ofprostaglandins which have been identified as one of the causative agentsof cystoid macular edema. Additionally, corticosteroids includingdexamethasone have also been shown to have potent anti-permeabilityactivity by inhibiting the synthesis of VEGF. Despite knownanti-inflammatory and anti-permeability properties, use ofcorticosteroid in the treatment of macular edema has been limitedbecause of the inability to deliver and to maintain adequate quantitiesof the drugs at the macular without resultant toxicities.

Previously, dexamethasone use has yielded varying degrees of success intreating retinal disorders including macular edema largely due to theinability to deliver and maintain adequate quantities of the drug to theposterior segment (vitreous) without resultant toxicities. Topicaladministration of 1 drop (50 μl) of a 0.1% dexamethasone ophthalmicsuspension, 4 times a day is equivalent to approximately 200 μg per day,however, only about 1% (2 μg per day) reaches the anterior segment, andonly a fraction of that amount moves into the posterior segment(vitreous). Although intravitreal injections of dexamethasone have beenused, the exposure of the drug is very temporal as the half-life of thedrug within the eye is approximately 3 hours, Periocular and posteriorsub-Tenon's injections of dexamethasone have been used, but with onlyshort-term treatment effect.

Treatment with corticosteroids must be monitored closely due topotential toxicity and long-term side effects. Adverse reactions listedfor conventional ophthalmic dexamethasone preparations include: glaucoma(with optic nerve damage, visual acuity and field defects), posteriorsubcapsular cataract formation, and secondary ocular infection frompathogens including herpes simplex. Systemic doses of dexamethasone canbe as high as 9000 μg/kg/day, of which only a small portion reaches theposterior segment, and may be associated with additional hazardousside-effects including hypertension, hyperglycemia, increasedsusceptibility to infection, and peptic ulcers.

Although an efficient means of delivering a drug to the posteriorsegment is direct delivery into the vitreous body, the naturalpharmacokinetics of the eye typically result in a short half-life unlessthe drug can be delivered using a formulation capable of providingsustained release. By delivering a drug intravitreally, the blood-eyebarrier is circumvented and intraocular therapeutic levels can beachieved without the risk of systemic toxicity.

An anti-inflammatory (i.e. immunosuppressive) agent can be used for thetreatment of an ocular condition which involves inflammation, such as anuveitis or macula edema. Thus, topical or oral glucocorticoids have beenused to treat uveitis. A major problem with topical and oral drugadministration is the inability of the drug to achieve an adequate (i.e.therapeutic) intraocular concentration. See e.g. Bloch-Michel E. (1992).Opening address: intermediate uveitis, In Intermediate Uveitis, Dev.Ophthalmol, W. R. F. Böke et al. editors., Basel: Karger, 23:1-2; Pinar,V., et al. (1997). Intraocular inflammation and uveitis” In Basic andClinical Science Course. Section 9 (1997-1998) San Francisco: AmericanAcademy of Ophthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992).Clinical picture of intermediate uveitis, In Intermediate Uveitis, Dev.Ophthalmol. W. R. F. Böke et al. editors., Basel: Karger, 23:20-7; andCheng C-K et al. (1995). Intravitreal sustained-release dexamethasonedevice in the treatment of experimental uveitis, Invest. Ophthalmol.Vis. Sci. 36:442-53.

Systemic glucocorticoid administration can be used alone or in additionto topical glucocorticoids for the treatment of uveitis. However,prolonged exposure to high plasma concentrations (administration ofprednisone 1 mg/kg/day for 2-3 weeks) of steroid is often necessary sothat therapeutic levels can be achieved in the eye.

Unfortunately, these high drug plasma levels commonly lead to systemicside effects such as hypertension, hyperglycemia, increasedsusceptibility to infection, peptic ulcers, psychosis, and othercomplications. Cheng C-K et al. (1995). Intravitreal sustained-releasedexamethasone device in the treatment of experimental uveitis, Invest.Ophthalmol. Vis. Sci. 36:442-53; Schwartz, B. (1966). The response ofocular pressure to corticosteroids, Ophthalmol. Clin. North Am.6:929-89; Skalka, H. W. et al. (1980). Effect of corticosteroids oncataract formation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al.(1992). Ocular effects of topical and systemic steroids, DermatologicClinics 10:505-12.

Additionally, delivery to the eye of a therapeutic amount of an activeagent can be difficult, if not impossible, for drugs with short plasmahalf-lives since the exposure of the drug to intraocular tissues islimited. Therefore, a more efficient way of delivering a drug to treat aposterior ocular condition is to place the drug directly in the eye,such as directly into the vitreous. Maurice, D. M. (1983).Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee,V. H. L. et al. (1989). Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby,Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995). Human scleralpermeability: effects of age, cryotherapy, transscleral diode laser, andsurgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.

Techniques such as intravitreal injection of a drug have shown promisingresults, but due to the short intraocular half-life of active agent,such as the glucocorticoid dexamethasone (approximately 3 hours),intravitreal injections must be frequently repeated to maintain atherapeutic drug level. In turn, this repetitive process increases thepotential for side effects such as retinal detachment, endophthalmitis,and cataracts. Maurice, D. M. (1983). Micropharmaceutics of the eye,Ocular Inflammation Ther. 1:97-102; Olsen, T. W. et al. (1995). Humanscleral permeability: effects of age, cryotherapy, transscleral diodelaser, and surgical thinning, Invest. Ophthalmol. Vis. Sci.36:1893-1903; and Kwak, H. W. and D'Amico, D. J. (1992). Evaluation ofthe retinal toxicity and pharmacokinetics of dexamethasone afterintravitreal injection, Arch. Ophthalmol. 110:259-66.

Additionally, topical, systemic, and periocular glucocorticoid treatmentmust be monitored closely due to toxicity and the long-term side effectsassociated with chronic systemic drug exposure sequelae. Rao, N. A. etal. (1997). Intraocular inflammation and uveitis, In Basic and ClinicalScience Course. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). Theresponse of ocular pressure to corticosteroids, Ophthalmol Clin North Am6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect ofcorticosteroids on cataract formation, Arch Ophthalmol 98:1773-7;Renfro, L and Snow, J. S. (1992). Ocular effects of topical and systemicsteroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). Acomparison of intraocular pressure elevating activity of loteprednoletabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.

U.S. Pat. No. 6,217,895 discusses a method of administering acorticosteroid to the posterior segment of the eye, but does notdisclose a bioerodible implant.

U.S. Pat. No. 5,501,856 discloses controlled release pharmaceuticalpreparations for intraocular implants to be applied to the interior ofthe eye after a surgical operation for disorders in retina/vitreous bodyor for glaucoma.

U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic andhydrophobic entities in a biodegradable sustained release implant, anddescribes a polylactic acid polyglycolic acid (PLGA) copolymer implantcomprising dexamethasone. As shown by in vitro testing of the drugrelease kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implantdisclosed did not show appreciable drug release until the beginning ofthe fourth week, unless a release enhancer, such as HPMC was added tothe formulation.

U.S. Pat. No. 5,824,072 discloses implants for introduction into asuprachoroidal space or an avascular region of the eye, and describes amethylcellulose (i.e. non-biodegradable) implant comprisingdexamethasone. WO 9513765 discloses implants comprising active agentsfor introduction into a suprachoroidal or an avascular region of an eyefor therapeutic purposes.

U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocularimplants comprising microencapsulated drugs, and describes implantingmicrocapsules comprising hydrocortisone succinate into the posteriorsegment of the eye.

U.S. Pat. No. 5,164,188 discloses encapsulated agents for introductioninto the suprachoroid of the eye, and describes placing microcapsulesand plaques comprising hydrocortisone into the pars plana. U.S. Pat.Nos. 5,443,505 and 5,766,242 disclose implants comprising active agentsfor introduction into a suprachoroidal space or an avascular region ofthe eye, and describes placing microcapsules and plaques comprisinghydrocortisone into the pars plana.

Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine,triamcinolone, and human recombinant tissue plasminogen activator forintraocular management of proliferative vitreoretinopathy (PVR). Zhou,T, et al. (1998). Development of a multiple-drug delivery implant forintraocular management of proliferative vitreoretinopathy, Journal ofControlled Release 55: 281-295.

U.S. Pat. No. 6,046,187 discusses methods and compositions formodulating local anesthetic by administering one or moreglucocorticosteroid agents before, simultaneously with or after theadministration of a local anesthetic at a site in a patient.

U.S. Pat. No. 3,986,510 discusses ocular inserts having one or moreinner reservoirs of a drug formulation confined within a bioerodibledrug release rate controlling material of a shape adapted for insertionand retention in the “sac of the eye,” which is indicated as beingbounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the eyelid, or for placementover the corneal section of the eye.

U.S. Pat. No. 6,369,116 discusses an implant with a release modifierinserted within a scleral flap.

EP 0 654256 discusses use of a scleral plug after surgery on a vitreousbody, for plugging an incision.

U.S. Pat. No. 4,863,457 discusses the use of a bioerodible implant toprevent failure of glaucoma filtration surgery by positioning theimplant either in the subconjunctival region between the conjunctivalmembrane overlying it and the sclera beneath it or within the scleraitself within a partial thickness sclera flap.

EP 488 401 discusses intraocular implants, made of certain polylacticacids, to be applied to the interior of the eye after a surgicaloperation for disorders of the retina/vitreous body or for glaucoma.

EP 430539 discusses use of a bioerodible implant which is inserted inthe suprachoroid.

Significantly, it is known that PLGA co-polymer formulations of abioerodible polymer comprising an active agent typically release theactive agent with a characteristic sigmoidal release profile (as viewedas time vs percent of total active agent released), that is after arelatively long initial lag period (the first release phase) when littleif any active agent is released, there is a high positive slope periodwhen most of the active agent is released (the second release phase)followed by another near horizontal (third) release phase, when the drugrelease reaches a plateau.

Thus, there is a need for a extended therapeutic treatment of an ocularcondition, such as posterior ocular condition. In particular, there is aneed for treatment over an extended duration, for example, time periodsextending up to 60 days, 90 days, 120 days, 6 months, 8 months, 12months or more, after release of a therapeutic amount of a drug at anocular site, such as the vitreous. Such extended treatment with anactive agent can be advantageous to prevent recurrence of theinflammatory or other posterior ocular condition treated. It can alsominimize the number of surgical interventions required by the patientover time to treat an ocular condition.

SUMMARY

The present invention meets these and other needs and provides formethods and implants which can provide an extended treatment of anocular condition after release of a therapeutic amount of a drug from animplant placed in the vitreous and with maintenance of such atherapeutic effect for an extended period during which a therapeuticlevel or amount of the drug is not present is not detectable in thevitreous.

DEFINITIONS

The following terms as used herein have the following meanings:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means±10% of the numerical value orrange recited or claimed.

“Active agent” and “drug” are used interchangeably and refer to anysubstance used to treat an ocular condition.

“Anterior ocular condition” means a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularsite, such as a periocular muscle, an eye lid or an eye ball tissue orfluid which is located anterior to the posterior wall of the lenscapsule or ciliary muscles. Thus, an anterior ocular condition primarilyaffects or involves, the conjunctiva, the cornea, the conjunctiva, theanterior chamber, the iris, the posterior chamber (behind the iris butin front of the posterior wall of the lens capsule), the lens or thelens capsule and blood vessels and nerve which vascularize or innervatean anterior ocular region or site.

“Bioerodible polymer” means a polymer which degrades in vivo, andwherein erosion of the polymer over time is required to release theactive agent. The words “bioerodible” and “biodegradable” are synonymousand are used interchangeably herein.

“Extended” as in “extended therapeutic effect” means for a period oftime greater than thirty days after release of all or all substantiallyall of an active agent in vivo from an intraocular implant. Morepreferably the extended therapeutic effect persists for at least 60 daysafter release of all or all substantially all of an active agent in vivofrom an intraocular implant.

“Glaucoma” means primary, secondary and/or congenital glaucoma. Primaryglaucoma can include open angle and closed angle glaucoma. Secondaryglaucoma can occur as a complication of a variety of other conditions,such as injury, inflammation, vascular disease and diabetes.

“Inflammation-mediated” in relation to an ocular condition means anycondition of the eye which can benefit or potentially benefit fromtreatment with an anti-inflammatory agent, and is meant to include, butis not limited to, uveitis, macular edema, acute macular degeneration,retinal detachment, ocular tumors, fungal or viral infections,multifocal choroiditis, diabetic uveitis, proliferativevitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada(VKH) syndrome, histoplasmosis, and uveal effusion.

“Injury” or “damage” are interchangeable and refer to the cellular andmorphological manifestations and symptoms resulting from aninflammatory-mediated condition, such as, for example, inflammation.

“Measured under infinite sink conditions in vitro,” means assays tomeasure drug release in vitro, wherein the experiment is designed suchthat the drug concentration in the receptor medium never exceeds 5% ofsaturation. Examples of suitable assays may be found, for example, inUSP 23; NF 18 (1995) pp. 1790-1798.

“Ocular condition” means a disease, aliment or condition which affectsor involves the eye or one or the parts or regions of the eye, such as aretinal disease. The eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

“Retinopathy” means a disorder or disease of the retina. Such an diseaseor disorder may be associated with an overlying condition such asglaucoma, macular edema, dry and wet macular degeneration, diabeticretinopathy, at the like.

“Posterior ocular condition” means a disease, ailment or condition whichaffects or involves a posterior ocular region or site such as choroid orsclera (in a position posterior to a plane through the posterior wall ofthe lens capsule), vitreous, vitreous chamber, retina, optic nerve(including the optic disc), and blood vessels and nerve whichvascularize or innervate a posterior ocular region or site.

“Steroidal anti-inflammatory agent” and “glucocorticoid” are usedinterchangeably herein, and are meant to include steroidal agents,compounds or drugs which reduce inflammation when administered at atherapeutically effective level.

“Substantially” means at least 51%. A release of substantially all of anactive agent occurs when, at least 24 hours after in vivo insertion ofan intraocular implant, a therapeutic amount of the active agent is notpresent in the vitreous. A release of essentially all of an active agentis deemed to occur when, at least 24 hours after in vivo insertion of anintraocular implant, a detectable amount of the active agent is notpresent in the vitreous. “Substantially” in relation to the blending,mixing or dispersing of an active agent in a polymer, as in the phrase“substantially homogenously dispersed” means that there are no oressentially no particles (i.e. aggregations) of active agent in such ahomogenous dispersal.

“Suitable for insertion (or implantation) in (or into) an ocular regionor site” with regard to an implant, means an implant which has a size(dimensions) such that it can be inserted or implanted without causingexcessive tissue damage and without unduly physically interfering withthe existing vision of the patient into which the implant is implantedor inserted.

A method according to the present invention can be carried out using animplant suitable for insertion, placement or implantation at an ocularsite, such as the vitreous. Suitable implant can be made using themethods and materials set forth in U.S. patent application Ser. No.10/340,237.

The present invention encompasses a method for treating an ocularcondition. The method can have the steps of firstly inserting an implantinto an ocular site of a patient with an ocular condition. The implantcan be made of an active agent, and a carrier associated with the activeagent. The carrier can be a polymer or a bioceramic material. Thecarried can be associated with the active agent by mixing the activeagent and the carrier, dispersing the active agent in the carrier,encapsulating the active agent by the carrier, incorporating the activeagent within the carrier, and the like.

The next (second) step in the method can be releasing substantially allof the active agent from the implant. The third step in the method canbe obtaining an improvement in the ocular condition at a time when atherapeutic amount of the active agent is not present at the ocularsite. A fourth step in the method can be maintaining the improvement inthe ocular condition for an extended period of time during which atherapeutic amount of the active agent is not present at the ocularsite.

The releasing (second) step can occur over a first period of time X, andthe subsequent extended period of time during which an improvement inthe ocular condition is maintained, although a therapeutic amount of theactive agent is not present at the ocular site, is a second period oftime between 0.5× and 100×. The first period of time can be betweenabout 30 days and about 40 days, such as about 35 days. The secondperiod of time can be between about 30 days and about 180 days.

The active agent can be an anti-inflammatory agent and the carrier canbe a bioerodible polymer. The implant can have a weight between about 1μg and about 100 mg. The implant can have no dimension less than about0.1 mm and no dimension greater than about 20 mm. The implant can have avolume of from about 1 mm³ to about 100 mm³, but preferably the implanthas a volume of between about 5-20 mm³.

The improvement of the ocular condition obtained by a method within thescope of the present invention can be determined by observing animproved visual acuity, by observing an improved visual contrastsensitivity, by observing a decreased retinal or choroidal blood vesselleakage, by observing a decreased retinal or macular thickness, or byobserving a reduced number of cells in the aqueous or vitreous humor orby determining a reduced flare.

The improvement in the ocular condition can occur at a time when adetectable amount of the active agent is not present at the ocular site.The ocular site can be vitreous and the active agent can bedexamethasone.

Another method within the scope of the present invention is a method fortreating a chronic ocular condition by (a) inserting an implant into anocular site of a patient with an ocular condition, the implantcomprising (i) an active agent, and (ii) a carrier associated with theactive agent; (b) releasing substantially all of the active agent fromthe implant; (c) obtaining an improvement in the ocular condition at atime when a therapeutic amount of the active agent is not present at theocular site, and; (d) maintaining the improvement in the ocularcondition for an extended period of time during which a therapeuticamount of the active agent is not present at the ocular site.

A further method within the scope of the present invention is a methodfor treating an inflammatory posterior ocular condition by (a) insertinga biodegradable implant into a posterior ocular site of a patient withan inflammatory posterior ocular condition, the biodegradable implantcomprising (i) an anti-inflammatory active agent mixed with (ii) abiodegradable polymer; (b) releasing substantially all of theanti-inflammatory active agent from the biodegradable implant; (c)obtaining an improvement in the inflammatory posterior ocular conditionat a time when a therapeutic amount of the anti-inflammatory activeagent is not present at the posterior ocular site, and; (d) maintainingthe improvement in the inflammatory ocular condition for an extendedperiod of time during which a therapeutic amount of theanti-inflammatory active agent is not present at the posterior ocularsite. The inserting step is preferably carried out by insertion of theimplant through the pars plana and adjacent thereto in the vitreouscavity. Alternately, the insertion step can be carried out by placingthe biodegradable implant into the vitreous about 2 mm to about 6 mmanterior of the macular and not along the visual axis of incoming lightthrough the pupil

A detailed method within the scope of the present invention is a methodfor treating persistent macular edema (a) inserting a biodegradableimplant deep into the vitreous of a patient with persistent macularedema, the biodegradable implant comprising (i) dexamethasone mixed with(ii) a bioerodible PLGA co-polymer; (b) releasing all of thedexamethasone from the biodegradable implant; (c) obtaining animprovement in the persistent macular edema at a time when a therapeuticamount of the dexamethasone is not present in the vitreous, and; (d)maintaining the improvement in the persistent macular edema for anextended period of time during which a therapeutic amount of thedexamethasone is not present in the vitreous. The inserting step ispreferably carried out by insertion of the implant through the parsplana and adjacent thereto in the vitreous cavity. Alternately, theinsertion step can be carried out by placing the biodegradable implantinto the vitreous about 2 mm to about 6 mm anterior of the macular andnot along the visual axis of incoming light through the pupil. Thereleasing step can comprise releasing between about 350 700 μg ofdexamethasone from the biodegradable implant. Additionally, thereleasing step can entail releasing about 700 μg of dexamethasone fromthe biodegradable implant within about 30 days to 40 days after theinserting step. Notably, the obtaining step can comprise obtaining animprovement in the visual acuity of the patient. The improvement in thevisual acuity of the patient can be obtained within about 30 days toabout 180 days after the inserting step. Significantly, the maintainingstep, by which the improvement in the visual acuity of the patient withpersistent macular edema can be maintained for an extended period oftime during which a therapeutic amount of the dexamethasone is notpresent in the vitreous, is a period of time of about 30 days to about150 days after the obtaining step.

A preferred method within the scope of the present invention is a methodfor improving the visual acuity of a patient with persistent macularedema by (a) inserting a biodegradable implant into the vitreous of apatient with persistent macular edema by inserting the biodegradableimplant through the pars plana and adjacent thereto in the vitreouscavity or alternately, the insertion step can be carried out by placingthe biodegradable implant into the vitreous about 2 mm to about 6 mmanterior of the macular and not along the visual axis of incoming lightthrough the pupil, the biodegradable implant comprising (i) about350-700 μg dexamethasone mixed with (ii) a bioerodible PLGA co-polymer;(b) releasing the 350-700 μg of dexamethasone from the biodegradableimplant within about 30 days to about 40 days after the inserting step;(c) obtaining an improvement in the visual acuity of the patient withthe persistent macular edema at a time within about 30 days and 180 daysafter the inserting step during which time when a therapeutic amount ofthe dexamethasone is not present in the vitreous, and; (d) maintainingthe improvement in the visual acuity of the patient with the persistentmacular edema for about 30 days to about 150 days after the obtainingstep during a time when a therapeutic amount of the dexamethasone is notpresent in the vitreous.

The present invention also includes a method for treating an ocularcondition by inserting an implant into the vitreous cavity of a patientwith an ocular condition, the implant comprising (i) a steroid, and (ii)a carrier associated with the steroid; followed by releasingsubstantially all of the steroid from the implant, and then obtaining animprovement in the ocular condition with no increase in intraocularpressure in the patient above about 25 mm Hg, where the patient had abaseline (i.e. prior to implant insertion) IOP of less or equal to about25 mm Hg.

The present invention also includes a method for treating an ocularcondition by inserting an implant into the vitreous cavity of a patientwith an ocular condition, the implant comprising (i) a steroid, and (ii)a carrier associated with the steroid; followed by releasingsubstantially all of the steroid from the implant, and then obtaining animprovement in the ocular condition with no occurrence of an ocularcataract in the patient subsequent to insertion of the implant.

DRAWINGS

FIG. 1 is a graph showing vitreous humor concentrations (ng/ml) ofdexamethasone over a period of 72 hours for two tabletted implants (350μg or 700 μg of dexamethasone) and for two extrusion formed implants(350 μg or 700 μg of dexamethasone)

FIG. 2 is a graph showing cumulative percent of dexamethasone releasedinto the vitreous humor over a period of 72 hours for two tablettedimplants (350 μg or 700 μg of dexamethasone) and for two extrusionformed implants (350 μg or 700 μg of dexamethasone)

FIG. 3 is a graph showing vitreous humor concentrations (ng/ml) ofdexamethasone over a period of 84 days for two tabletted implants (350μg or 700 μg of dexamethasone) and for two extrusion formed implants(350 μg or 700 μg of dexamethasone)

FIG. 4 is a graph showing cumulative percent of dexamethasone releasedinto the vitreous humor over a period of 84 days for two tablettedimplants (350 μg or 700 μg of dexamethasone) and for two extrusionformed implants (350 μg or 700 μg of dexamethasone.

FIG. 5 illustrates diagrammatically a cross-sectional view of an eye.

DESCRIPTION

The present invention is based upon the discovery of methods forobtaining and for maintaining a therapeutic treatment of an ocularcondition during a period of time during which a therapeutic amount ofan active agent is not present. A method within the scope of the presentinvention can be carried out by inserting an implant comprising anactive agent into an ocular site of a patient. Over a first period oftime the implant then releases all of it's active agent. There is thenobtained an amelioration of a manifestation or of a symptom of theocular condition (i.e. a therapeutic effect) for a second period of timeduring which a detectable or therapeutic amount of the active agent isnot present at the ocular site.

It is generally accepted that treatment of a chronic ocular conditionrequires chronic administration of a therapeutic amount of a suitableactive agent. Glaucoma is a chronic ocular condition characterized byhigh (i.e. greater than 25 mm Hg) intra ocular (aqueous humor) pressure.It is known that if a patient receiving topical (i.e. applied as eyedrops) anti-glaucoma medication stops using the topical anti-glaucomamedication his intraocular pressure (“IOP”) will quickly revert to itsformer (baseline) high (unmedicated) intraocular pressure raise. Theperiod for return to baseline IOP is referred to as the washout period.Well before the conclusion of the washout period (i.e. usually after afew hours or at most a few days) of time there is no longer atherapeutic amount or a detectable amount of the active agent inquestion present for treatment of the ocular condition. Thus the termwashout refers to the time period required for return to substantially abaseline (pre-therapeutic) condition, not to the time period requiredfor removal of the active agent. The washout period for topicalbeta-blocker anti-glaucoma medication is about four weeks. The washoutperiod for topical sympathomimetics (stimulating alpha and betareceptors; i.e. epinephrine) anti-glaucoma medication is about threeweeks. The washout period for topical miotics (i.e. pilocarpine)anti-glaucoma medication is about 48 hours. Marcon, I., A double-maskedcomparison of betaxolol and levobunolol for the treatment of primaryopen-angle glaucoma, Arq Bras Oftalmol 1990; 53(1):27-32.

Additionally, it is known that the washout period for topical carbonicanhydrase inhibitor (i.e. dorzolamide) anti-glaucoma medication is twoto four weeks, and that the washout period for alpha adrenergic receptoragonists (i.e. brimonidine) is also about two to four weeks. Molfino,F., et al., IOP-lowering effect of dorzolamide 2% versus brimonidinetartrate 0.2%. A prospective randomized cross over study, InvestOphthalmol V is Sci 1998 Mar. 15; 39(4):S481. The washout period forbrimonidine may be as long as five weeks and as long as eight weeks fora prostaglandin (i.e. latanoprost) anti-glaucoma medication. Stewart,W., et al., Washout periods for brimonidine 0.2% and latanoprost 0.005%,Am J Ophthalmol 2001 June; 131(6):798-799.

To confirm and to supplement the existence of washout periods, threedifferent population of patients with glaucoma were examined, as setforth by Example A, supra. The results set forth by Example A show thatwithin a short period of a day or two after stopping chronic use ofvarious anti-glaucoma medications, the mean intraocular pressure of allpatient populations increased significantly, thereby showing that achronic intraocular condition requires chronic treatment to obtain anongoing therapeutic effect.

Thus, it was surprising and unexpected to discover that methods withinthe scope of the present invention permit ongoing therapeutic treatmentof a chronic ocular condition for an extended period of time after thewashout period—when both a therapeutic level of the active agent is(long since) no longer present and by which time it was expected that areturn or a substantial return to a baseline condition (i.e. as assessedprior to commencement of therapy) should have occurred in the patients.Specifically, prior to the present invention it was thought thatcontinuous and prolonged therapy (i.e. chronic active agent [i.e.steroid] administration) was required to treat a chronic ocularcondition.

The present invention thereby permits an ocular condition to be treatedwith use of less active agent for a shorter duration with fewer sideeffects and complications, as compared to a treatment of the same ocularcondition with the same active agent administered as a non-implantformulation (i.e. as a liquid intravitreal injection). Thus, the presentinvention permits a short term treatment (i.e. release of an activeagent from an intra-vitreal implant over 10-40 days) to provide a longterm therapeutic benefit (i.e. for 150 days or longer after all theactive agent has been released from the implant) with fewer side effectsand fewer complications due to removal of the need for chronic dosing.Thus a desired clinical (therapeutic) effect such as lower IOP, lessinflammation, decreased retinal thickness, increased visual acuity,increased visual contract sensitivity, reduced retinal and/or choriodalblood vessel leakage can be obtained and maintained for an extendedperiod of time (i.e. about 6 months or longer) after intra-vitrealrelease (i.e. after a sustained release over 10-40 days) of all theactive agent.

The present invention encompasses biodegradable ocular implants andimplant systems and methods of using such implants and implant systemsfor treating posterior ocular conditions. The implants can be formed tobe monolithic, that is the active agent is homogenously distributed ordispersed throughout the biodegradable polymer matrix. Additionally, theimplants can are formed to release an active agent into an ocular regionof the eye over various time periods. Thus, the active agent can bereleased from implants made according to the present invention for aperiod of time of, for example, 30-40 days.

Biodegradable Implants for Treating an Ocular Condition

The implants of the present invention can include an active agent mixedwith or dispersed within a biodegradable polymer. The implantcompositions can vary according to the preferred drug release profile,the particular active agent used, the ocular condition being treated,and the medical history of the patient. Active agents that may be usedinclude, but are not limited to (either by itself in an implant withinthe scope of the present invention or in combination with another activeagent): ace-inhibitors, endogenous cytokines, agents that influencebasement membrane, agents that influence the growth of endothelialcells, adrenergic agonists or blockers, cholinergic agonists orblockers, aldose reductase inhibitors, analgesics, anesthetics,antiallergics, anti-inflammatory agents, antihypertensives, pressors,antibacterials, antivirals, antifungals, antiprotozoals,anti-infectives, antitumor agents, antimetabolites, antiangiogenicagents, tyrosine kinase inhibitors, antibiotics such as aminoglycosidessuch as gentamycin, kanamycin, neomycin, and vancomycin; amphenicolssuch as chloramphenicol; cephalosporins, such as cefazolin HCl;penicillins such as ampicillin, penicillin, carbenicillin, oxycillin,methicillin; lincosamides such as lincomycin; polypeptide antibioticssuch as polymixin and bacitracin; tetracyclines such as tetracycline;quinolones such as ciproflaxin, etc.; sulfonamides such as chloramine T;and sulfones such as sulfanilic acid as the hydrophilic entity,anti-viral drugs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, dideoxyinosine, dideoxycytosine, dexamethasone,ciproflaxin, water soluble antibiotics, such as acyclovir, gancyclovir,vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine;epinephrine; isoflurphate; adriamycin; bleomycin; mitomycin; ara-C;actinomycin D; scopolamine; and the like, analgesics, such as codeine,morphine, keterolac, naproxen, etc., an anesthetic, e.g. lidocaine;.beta.-adrenergic blocker or .beta.-adrenergic agonist, e.g. ephidrine,epinephrine, etc.; aldose reductase inhibitor, e.g. epalrestat,ponalrestat, sorbinil, tolrestat; antiallergic, e.g. cromolyn,beclomethasone, dexamethasone, and flunisolide; colchicine,anihelminthic agents, e.g. ivermectin and suramin sodium; antiamebicagents, e.g. chloroquine and chlortetracycline; and antifungal agents,e.g. amphotericin, etc., anti-angiogenesis compounds such as anecortaveacetate, retinoids such as Tazarotene, anti-glaucoma agents, such asbrimonidine (Alphagan and Alphagan P), acetozolamide, bimatoprost(Lumigan), Timolol, mebefunolol; memantine; alpha-2 adrenergic receptoragonists; 2ME2; anti-neoplastics, such as vinblastine, vincristine,interferons; alpha., beta. and .gamma., antimetabolites, such as folicacid analogs, purine analogs, and pyrimidine analogs; immunosuppressantssuch as azathiprine, cyclosporine and mizoribine; miotic agents, such ascarbachol, mydriatic agents such as atropine, etc., protease inhibitorssuch as aprotinin, camostat, gabexate, vasodilators such as bradykinin,etc., and various growth factors, such epidermal growth factor, basicfibroblast growth factor, nerve growth factors, and the like.

In one variation the active agent is methotrexate. In another variation,the active agent is a retinoic acid. In another variation, the activeagent is an anti-inflammatory agent such as a nonsteroidalanti-inflammatory agent. Nonsteroidal anti-inflammatory agents that maybe used include, but are not limited to, aspirin, diclofenac,flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a furthervariation, the anti-inflammatory agent is a steroidal anti-inflammatoryagent, such as dexamethasone.

Steroidal Anti-Inflammatory Agents

The steroidal anti-inflammatory agents that may be used in the ocularimplants include, but are not limited to, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and any of their derivatives.

In one embodiment, cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone, and their derivatives, are preferred steroidalanti-inflammatory agents. In another preferred variation, the steroidalanti-inflammatory agent is dexamethasone. In another variation, thebiodegradable implant includes a combination of two or more steroidalanti-inflammatory agents.

The active agent, such as a steroidal anti-inflammatory agent, cancomprise from about 10% to about 90% by weight of the implant. In onevariation, the agent is from about 40% to about 80% by weight of theimplant. In a preferred variation, the agent comprises about 60% byweight of the implant. In a more preferred embodiment of the presentinvention, the agent can comprise about 50% by weight of the implant.

Biodegradable Polymers

In one variation, the active agent can be homogeneously dispersed in thebiodegradable polymer of the implant. The implant can be made, forexample, by a sequential or double extrusion method. The selection ofthe biodegradable polymer used can vary with the desired releasekinetics, patient tolerance, the nature of the disease to be treated,and the like. Polymer characteristics that are considered include, butare not limited to, the biocompatibility and biodegradability at thesite of implantation, compatibility with the active agent of interest,and processing temperatures. The biodegradable polymer matrix usuallycomprises at least about 10, at least about 20, at least about 30, atleast about 40, at least about 50, at least about 60, at least about 70,at least about 80, or at least about 90 weight percent of the implant.In one variation, the biodegradable polymer matrix comprises about 40%to 50% by weight of the implant.

Biodegradable polymers which can be used include, but are not limitedto, polymers made of monomers such as organic esters or ethers, whichwhen degraded result in physiologically acceptable degradation products.Anhydrides, amides, orthoesters, or the like, by themselves or incombination with other monomers, may also be used. The polymers aregenerally condensation polymers. The polymers can be crosslinked ornon-crosslinked. If crosslinked, they are usually not more than lightlycrosslinked, and are less than 5% crosslinked, usually less than 1%crosslinked.

For the most part, besides carbon and hydrogen, the polymers willinclude oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen can be present as amide, cyano, and amino. An exemplary list ofbiodegradable polymers that can be used are described in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: “CRC CriticalReviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRC Press, BocaRaton, Fla. (1987).

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof. Copolymers of glycolic and lactic acid are ofparticular interest, where the rate of biodegradation is controlled bythe ratio of glycolic to lactic acid. The percent of each monomer inpoly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about15-85%, about 25-75%, or about 35-65%. In certain variations, 25/75 PLGAand/or 50/50 PLGA copolymers are used. In other variations, PLGAcopolymers are used in conjunction with polylactide polymers.

Biodegradable polymer matrices that include mixtures of hydrophilic andhydrophobic ended PLGA may also be employed, and are useful inmodulating polymer matrix degradation rates. Hydrophobic ended (alsoreferred to as capped or end-capped) PLGA has an ester linkagehydrophobic in nature at the polymer terminus. Typical hydrophobic endgroups include, but are not limited to alkyl esters and aromatic esters.Hydrophilic ended (also referred to as uncapped) PLGA has an end grouphydrophilic in nature at the polymer terminus. PLGA with a hydrophilicend groups at the polymer terminus degrades faster than hydrophobicended PLGA because it takes up water and undergoes hydrolysis at afaster rate (Tracy et al., Biomaterials 20:1057-1062 (1999)). Examplesof suitable hydrophilic end groups that may be incorporated to enhancehydrolysis include, but are not limited to, carboxyl, hydroxyl, andpolyethylene glycol. The specific end group will typically result fromthe initiator employed in the polymerization process. For example, ifthe initiator is water or carboxylic acid, the resulting end groups willbe carboxyl and hydroxyl. Similarly, if the initiator is amonofunctional alcohol, the resulting end groups will be ester orhydroxyl.

Additional Agents

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Preservatives which may be used include, but are not limitedto, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. Examples of buffering agents that may be employed include, butare not limited to, sodium carbonate, sodium borate, sodium phosphate,sodium acetate, sodium bicarbonate, and the like, as approved by the FDAfor the desired route of administration. Electrolytes such as sodiumchloride and potassium chloride may also be included in the formulation.

The biodegradable ocular implants can also include additionalhydrophilic or hydrophobic compounds that accelerate or retard releaseof the active agent. Additionally, release modulators such as thosedescribed in U.S. Pat. No. 5,869,079 can be included in the implants.The amount of release modulator employed will be dependent on thedesired release profile, the activity of the modulator, and on therelease profile of the glucocorticoid in the absence of modulator. Wherethe buffering agent or release enhancer or modulator is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug diffusion. Similarly,a hydrophobic buffering agent or enhancer or modulator can dissolve moreslowly, slowing the exposure of drug particles, and thereby slowing therate of drug diffusion.

Release Kinetics

An implant within the scope of the present invention can be formulatedwith an active agent (or a prodrug of an active agent) dispersed withina biodegradable polymer matrix. Without being bound by theory, it isbelieved that the release of the active agent can be achieved by erosionof the biodegradable polymer matrix and by diffusion of the particulateagent into an ocular fluid, e.g., the vitreous, with subsequentdissolution of the polymer matrix and release of the active agent.Factors which influence the release kinetics of active agent from theimplant can include such characteristics as the size and shape of theimplant, the size of the active agent particles, the solubility of theactive agent, the ratio of active agent to polymer(s), the method ofmanufacture, the surface area exposed, and the erosion rate of thepolymer(s). The release kinetics achieved by this form of active agentrelease are different than that achieved through formulations whichrelease active agents through polymer swelling, such as with crosslinkedhydrogels. In that case, the active agent is not released throughpolymer erosion, but through polymer swelling and drug diffusion, whichreleases agent as liquid diffuses through the pathways exposed.

The release rate of the active agent can depend at least in part on therate of degradation of the polymer backbone component or componentsmaking up the biodegradable polymer matrix. For example, condensationpolymers may be degraded by hydrolysis (among other mechanisms) andtherefore any change in the composition of the implant that enhanceswater uptake by the implant will likely increase the rate of hydrolysis,thereby increasing the rate of polymer degradation and erosion, and thusincreasing the rate of active agent release.

The release kinetics of the implants of the present invention can bedependent in part on the surface area of the implants. A larger surfacearea exposes more polymer and active agent to ocular fluid, causingfaster erosion of the polymer matrix and dissolution of the active agentparticles in the fluid. Therefore, the size and shape of the implant mayalso be used to control the rate of release, period of treatment, andactive agent concentration at the site of implantation. At equal activeagent loads, larger implants will deliver a proportionately larger dose,but depending on the surface to mass ratio, may possess a slower releaserate. For implantation in an ocular region, the total weight of theimplant preferably ranges, e.g., from about 200-15000 μg, usually fromabout 1000-5000 μg. In one variation, the total weight of the implant isabout 1200 to about 1,800 μg. In another variation, the total weight ofthe implant is about 2400 to about 3,600 μg. Preferably, the implant hasa weight between about 100 μg and about 2 mg.

The bioerodible implants are typically solid, and may be formed asparticles, sheets, patches, plaques, films, discs, fibers, rods, and thelike, or may be of any size or shape compatible with the selected siteof implantation, as long as the implants have the desired releasekinetics and deliver an amount of active agent that is therapeutic forthe intended medical condition of the eye. The upper limit for theimplant size will be determined by factors such as the desired releasekinetics, toleration for the implant at the site of implantation, sizelimitations on insertion, and ease of handling. For example, thevitreous chamber is able to accommodate relatively large rod-shapedimplants, generally having diameters of about 0.05 mm to 3 mm and alength of about 0.5 to about 10 mm. In one variation, the rods havediameters of about 0.1 mm to about 1 mm. In another variation, the rodshave diameters of about 0.3 mm to about 0.75 mm. In yet a furthervariation, other implants having variable geometries but approximatelysimilar volumes may also be used.

The proportions of active agent, polymer, and any other modifiers may beempirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration is after release is less than 20%,and preferably less than 5%, of saturation. The mixture is maintained at37° C. and stirred slowly to ensure drug diffusion after bioerosion. Theappearance of the dissolved drug as a function of time may be followedby various methods known in the art, such as spectrophotometrically,HPLC, mass spectroscopy, etc.

Applications

Examples of ocular conditions which can be treated by the implants andmethods of the invention include, but are not limited to, glaucoma,uveitis, macular edema, macular degeneration, retinal detachment, oculartumors, bacterial, fungal or viral infections, multifocal choroiditis,diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympatheticopthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uvealdiffusion, and vascular occlusion. In one variation, the implants areparticularly useful in treating such medical conditions as uveitis,macular edema, vascular occlusive conditions, proliferativevitreoretinopathy (PVR), and various other retinopathies.

Methods of Implantation

The biodegradable implants can be inserted into the eye by a variety ofmethods, including placement by forceps, by trocar, or by other types ofapplicators, after making an incision in the sclera. In some instances,a trocar or applicator may be used without creating an incision. In apreferred variation, a hand held applicator is used to insert one ormore biodegradable implants into the eye. The hand held applicatortypically comprises an 18-30 GA stainless steel needle, a lever, anactuator, and a plunger. Suitable devices for inserting an implant orimplants into a posterior ocular region or site includes those disclosedin U.S. patent application Ser. No. 10/666,872.

The method of implantation generally first involves accessing the targetarea within the ocular region with the needle, trocar or implantationdevice. Once within the target area, e.g., the vitreous cavity, a leveron a hand held device can be depressed to cause an actuator to drive aplunger forward. As the plunger moves forward, it can push the implantor implant into the target area (i.e. the vitreous).

Methods for Making Implants

Various techniques may be employed to make implants within the scope ofthe present invention. Useful techniques include phase separationmethods, interfacial methods, extrusion methods, compression methods,molding methods, injection molding methods, heat press methods and thelike.

Choice of the technique, and manipulation of the technique parametersemployed to produce the implants can influence the release rates of thedrug. Room temperature compression methods result in an implant withdiscrete microparticles of drug and polymer interspersed. Extrusionmethods result in implants with a progressively more homogenousdispersion of the drug within a continuous polymer matrix, as theproduction temperature is increased.

The use of extrusion methods allows for large-scale manufacture ofimplants and results in implants with a homogeneous dispersion of thedrug within the polymer matrix. When using extrusion methods, thepolymers and active agents that are chosen are stable at temperaturesrequired for manufacturing, usually at least about 50° C. Extrusionmethods use temperatures of about 25° C. to about 150° C., morepreferably about 60° C. to about 130° C.

Different extrusion methods may yield implants with differentcharacteristics, including but not limited to the homogeneity of thedispersion of the active agent within the polymer matrix. For example,using a piston extruder, a single screw extruder, and a twin screwextruder will generally produce implants with progressively morehomogeneous dispersion of the active. When using one extrusion method,extrusion parameters such as temperature, extrusion speed, die geometry,and die surface finish will have an effect on the release profile of theimplants produced.

In one variation of producing implants by a piston extrusion methods,the drug and polymer are first mixed at room temperature and then heatedto a temperature range of about 60° C. to about 150° C., more usually toabout 130° C. for a time period of about 0 to about 1 hour, more usuallyfrom about 0 to about 30 minutes, more usually still from about 5minutes to about 15 minutes, and most usually for about 10 minutes. Theimplants are then extruded at a temperature of about 60° C. to about130° C., preferably at a temperature of about 75° C.

In an exemplary screw extrusion method, the powder blend of active agentand polymer is added to a single or twin screw extruder preset at atemperature of about 80° C. to about 130° C., and directly extruded as afilament or rod with minimal residence time in the extruder. Theextruded filament or rod is then cut into small implants having theloading dose of active agent appropriate to treat the medical conditionof its intended use.

Implant systems according to the invention can include a combination ofa number of bioerodible implants, each having unique polymercompositions and drug release profiles that when co-administered providefor an extended continuous release of drug. Examples of fast releaseimplants include those made of certain lower molecular weight, fastdegradation profile polylactide polymers, such as R104 made byBoehringer Ingelheim GmbH, Germany, which is a poly(D,L-lactide) with amolecular weight of about 3,500. Examples of medium release implantsinclude those made of certain medium molecular weight, intermediatedegradation profile PLGA co-polymers, such as RG755 made by BoehringerIngelheim GmbH, Germany, which is a poly(D,L-lactide-co-glycolide withwt/wt 75% lactide:25% glycolide, a molecular weight of about 40,000 andan inherent viscosity of 0.50 to 0.70 dl/g. Examples of slow releaseimplants include those made of certain other high molecular weight,slower degradation profile polylactide polymers, such as R203/RG755 madeby Boehringer Ingelheim GmbH, Germany, for which the molecular weight isabout 14,000 for R203 (inherent viscosity of 0.25 to 0.35 dl/g) andabout 40,000 for RG755.

Examples of implants include those formed with RG755, R203, RG503,RG502, RG 502H as the first polymer, and RG502, RG 502H as the secondpolymer. Other polymers that can be used include PDL (poly(D,L-lactide))and PDLG (poly(D,L-lactide-co-glycolide)) polymers available from PURACAmerica, Inc. Lincolnshire, Ill. Poly(caprolactone) polymers can also beused. The characteristics of the specified polymers are (1) RG755 has amolecular weight of about 40,000, a lactide content (by weight) of 75%,and a glycolide content (by weight) of 25%; (2) R203 has a molecularweight of about 14,000, and a 100%; (30 RG503 has a molecular weight ofabout 28,000, a lactide content of 50%, and a glycolide content of 50%;(4) RG502 has a molecular weight of about 11,700 (inherent viscosity of0-16 to 0.24 dl/g), a lactide content of 50%, and a glycolide content of50%, and; (5) RG502H has a molecular weight of about 8,500, a lactidecontent of 50%, a glycolide content of 50% and free acid at the end ofpolymer chain.

Generally, if inherent viscosity is 0.16 the molecular weight is about6,327, and if the inherent viscosity is 0.28 the molecular weight isabout 20670.

According to our invention continual or substantially continual releaseof drug at levels corresponding to at least 10 ng/ml of dexamethasone ordexamethasone equivalent for between about 5-40 days can be achieved.

This may be more clearly understood with reference to FIG. 5 whichillustrates a cross-sectional view of a human eye 10 in order toillustrate the various sites that may be suitable for implantation of animplant in accordance with the present invention.

The eye 10 comprises a lens 12 and encompasses the vitreous chamber 14.Adjacent to the vitreous chamber is the optic part of the retina 16.Implantation may be into the vitreous 14, intraretinal 16 or subretinal18. The retina 16 is surrounded by the choroid 20. Implantation may beintrachoroidal or suprachoroidal 22. Between the optic part of theretina and the lens, adjacent to the vitreous, is the pars plana 24.Surrounding the choroid 20 is the sclera 26. Implantation may beintrascleral 26 or episcleral 28. The external surface of the eye is thecornea 30. Implantation may be epicorneal 30 or intra-corneal 32. On theexternal surface of the eye is the conjunctiva 34. Behind the cornea isthe anterior chamber 36, behind which is the lens 12. The posteriorchamber 38 surrounds the lens, as shown in the figure. Opposite from theexternal surface is the optic nerves, and the arteries and vein of theretina. Implants into the meningeal spaces 40, the optic nerve 42 andthe intraoptic nerve 44 allows for drug delivery into the centralnervous system, and provide a mechanism whereby the blood-brain barriermay be crossed.

Other sites of implantation include the delivery of antitumor drugs toneoplastic lesions, e.g. tumor, or lesion area, e.g. surroundingtissues, or in those situations where the tumor mass has been removed,tissue adjacent to the previously removed tumor and/or into the cavityremaining after removal of the tumor. The implants may be administeredin a variety of ways, including surgical means, injection, trocar, etc.

EXAMPLES

The following examples illustrate aspects and embodiments of theinvention.

Example A Rapid Loss of Therapeutic Effect Upon Cessation of OcularMedication

To examine loss or reduction of a therapeutic effect (i.e. IOP lowering)upon cessation of chronic medication administration used to treatment achronic ocular condition, three different populations of patients withglaucoma were examined.

1. A population of twenty patients with glaucoma was examined. It wasdetermined that on day 28 after the patients had been receiving topicalLumigan 0.03% once a day for three weeks and then twice a day for oneweek, the mean IOP on day 28 was −8 mm Hg from baseline. Yet on day 30after 2 days with no medication administered it was determined that themean IOP of the 20 patients was only −6 mm Hg from baseline.

2. Similarly for a separate population of 20 patients with glaucoma itwas determined that on day 28 after the patients had been receivingtopical timolol 0.5% twice a day for four weeks, the mean IOP on day 28was −4 mm Hg from baseline. Yet on day 30 after 2 days with nomedication administered the mean IOP of the 20 patients was only −2 mmHg from baseline.

3. For a separate (third) population of 18 patients with glaucoma it wasdetermined that on day 14 after the patients had been receiving topicalbrimonidine for 14 days, the mean IOP on day 14 was −2 mm Hg frombaseline. Yet on day 15 after 24 hours with no medication administeredthe mean IOP of the 18 patients was only −0.8 mm Hg from baseline.

The results set forth by Example A show that within a short period of aday or two after stopping chronic use of various anti-glaucomamedications, the mean intraocular pressure of all patient populationsincreased significantly, thereby showing that a chronic intraocularcondition requires chronic treatment to obtain an ongoing therapeuticeffect.

Example 1 Manufacture of Compressed Tablet Implants

Micronized dexamethasone (Pharmacia, Peapack, N.J.) and micronizedhydrophobic end 50/50 PLGA (Birmingham Polymers, Inc., Birmingham, Ala.)were accurately weighed and placed in a stainless steel mixing vessel.The vessel was sealed, placed on a Turbula mixer and mixed at aprescribed intensity, e.g., 96 rpm, and time, e.g., 15 minutes. Theresulting powder blend was loaded one unit dose at a time into asingle-cavity tablet press. The press was activated at a pre-setpressure, e.g., 25 psi, and duration, e.g., 6 seconds, and the tabletwas formed and ejected from the press at room temperature. The ratio ofdexamethasone to PLGA was 70/30 w/w for all compressed tablet implants.

Example 2 Manufacture of Extruded Implants

Micronized dexamethasone (Pharmacia, Peapack, N.J.) and unmicronizedPLGA were accurately weighed and placed in a stainless steel mixingvessel. The vessel was sealed, placed on a Turbula mixer and mixed at aprescribed intensity, e.g., 96 rpm, and time, e.g., 10-15 minutes. Theunmicronized PLGA composition comprised a 30/10 w/w mixture ofhydrophilic end PLGA (Boehringer Ingelheim, Wallingford, Conn.) andhydrophobic end PLGA (Boehringer Ingelheim, Wallingford, Conn.). Theresulting powder blend was fed into a DACA Microcompounder-Extruder(DACA, Goleta, Calif.) and subjected to a pre-set temperature, e.g.,115° C., and screw speed, e.g., 12 rpm. The filament was extruded into aguide mechanism and cut into exact lengths that corresponded to thedesignated implant weight. The ratio of dexamethasone to total PLGA(hydrophilic and hydrophobic end) was 60/40 w/w for all extrudedimplants.

Thus, the implant is composed of dexamethasone and a PLGA[poly(D,L-lactide-co glycolide)] polymer matrix. There are two sizes ofthe implant: one containing about 350 μg of dexamethasone and onecontaining about 700 μg of dexamethasone. Both sizes of implant contain60% by weight of drug and 40% by weight of polymer.

As set forth above, the implants can be manufactured by a continuousextrusion process by double extrusion using a twin-screw extruder. Theimplants can have a microstructure consisting of a micronizeddexamethasone particles homogeneously dispersed in a continuous polymermatrix.

The implants can be approximately cylindrical in shape. The 700 μgimplants can have a diameter of about 460 μm (0.460 mm) and a length ofabout 6 mm, and the 350 μg implant can have the same diameter and alength of about 3 mm.

The total weight of the 700 μg implants can be about 1.2 mg and thetotal weight of the 350 μg implant can be about 0.6 mg. Weight tolerancefor a population of implants can be about +10% by weight or less.

The PLGA polymer matrix can be a mixture of acid end and ester endpolymers. PLGA molecules are terminated at one end by an-OH (hydroxyl)group and at the other end by a —COOR group where for acid end moleculesR═H and for ester end molecules R=alkyl. The PLGA used in the Posurdex™implant can be a mixture of 75% by weight acid end PLGA and 25% byweight ester end PLGA. That is, the implants will be about 60% by weightdrug, about 30% by weight acid end PLGA, and about 10% by weight esterend PLGA. Both acid and ester end PLGA will contain 50% lactide unitsand 50% glycolide units.

Example 3 Method and Devices for Placing Implants into the Vitreous

Implants were placed into the posterior segment of the right eye of NewZealand White Rabbits by incising the conjunctiva and sclera between the10 and 12 o'clock positions with a 20-gauge microvitreoretinal (MVR)blade. Fifty to 100 μl, of vitreous humor was removed with a 1-ccsyringe fitted with a 27-gauge needle. A sterile trocar, preloaded withthe appropriate implant (drug delivery system, DDS), was inserted 5 mmthrough the sclerotomy, and then retracted with the push wire in place,leaving the implant in the posterior segment. Sclerae and conjunctivaewere than closed using a 7-0 Vicryl suture. Suitable applicators whichhave been used to place implants of Examples 1 and 2 in the vitreous ofhuman eyes are set forth in U.S. patent application Ser. No. 10/666,872.

Example 4 Comparison of Tablet and Extruded Dexamethasone BioerodibleVitreal Implants Over 72 Hours

Examples 4 and 5 set forth a pre-clinical study carried out to evaluatebiodegradable polymeric implants inserted in the posterior chamber (i.e.in the vitreous) of an eye. The implant contained the anti-inflammatorysteroid dexamethasone as the active agent. These implant are referred tobelow a “DEX PS DDS” implants. These implants and can be made as atablet (“T”) or as an extrusion (“E”), using a continuous extrusionprocess.

The dexamethasone can be used as the acetate salt or in the form of thesodium phosphate ester. In ophthalmology dexamethasone sodium phosphatehas been widely used for over 40 years as a topically applied solution(0.1%). The maximum safe dose of dexamethasone for intravitrealinjection or for release from an implanted sustained-release devices isbelieved to be about 4,800 μg to 5,000 μg. Thus, the total dose of 350μg or 700 μg delivered with the DEX PS DDS is a non-toxic dose. The testimplant DEX PS DDS is a polymeric matrix designed to deliverdexamethasone in vivo over a time period of approximately 35 days.

As set forth below, two animal studies were carried out (a 72 hour studyand an 84 day study), with the DEX PS DDS, using both a tablet (tabletedimplant) and an extruded form of the implant, to evaluate theintraocular and systemic pharmacokinetics (PK) of this intraocular drugdelivery system.

These experiments showed that both the tableted and extruded dosageforms can release 700 μg or 350 μg of dexamethasone over about the 35days it takes the implant to bioerode.

A 72 hour experiment was carried out to compare the pharmacokinetics oftableted and extruded forms at two dose levels of DEX PS DDS® uponimplantation into the posterior segment (vitreous) of the eyes of NewZealand white rabbits.

The four types of implants used in this experiment were designated as350 μg extruded DEX PS DDS (“350E”), 700 μg extruded DEX PS DDS(“700E”), 350 μg tableted DEX PS DDS (“350T”) and 700 μg tableted DEX PSDDS (“700T”).

On Day 0, 120 male New Zealand white rabbits each received 1 of the 4types of test implants (30 rabbits per test implant) in the posteriorsegment (vitreous) of the right eye. The left eye of each animal servedas a control. Euthanasia and necropsy were performed at 3, 6, 12, 24,and 72 hours after dosing. Prior to euthanasia, plasma was collected forevaluation of plasma dexamethasone concentrations. Aqueous and vitreoushumor samples were collected from the test and control eyes at necropsy,and the vitreous humor sample was divided into two sections. Theexperiment was carried out in compliance with Good Laboratory Practice(GLP Regulations, 21 CFR, Part 58). The section of the vitreous humorcontaining the DEX PS DDS remnant(s) was analyzed for dexamethasoneconcentrations and vitreous humor and aqueous humor of the treated eyewere assayed for dexamethasone concentrations, as was the vitreous andthe aqueous humor of the control eye, and the plasma.

No mortality occurred following implantation of the DEX PS DDS.Anesthesia and surgical recovery led to minor weight loss in 28 of 48animals necropsied at 24 and 72 hours, but no other morbidity wasreported during the experiment.

As shown by FIG. 1 concentration profiles in the vitreous humor weresimilar for the 350E and 700E implants of DEX PS DDS, with peak meanvitreous humor concentrations observed at 3 hours (194.65 ng/mL and912.33 ng/mL, respectively) and 6 hours (163.40 ng/mL and 918.50 ng/mL,respectively).

Mean dexamethasone concentrations with the extruded dosage form wereconsiderably higher for the 700 μg dose level than for the 350 μg doselevel. Between 6 and 24 hours, dexamethasone concentrations declined,and then, for the extruded implants, increased from 24 to 72 hours. Thispattern of drug release suggests that the initial concentrations ofdexamethasone observed in the vitreous resulted from surface release ofdexamethasone, which led to early peak mean concentrations. This initialpeak in concentration was followed by a decline in mean drugconcentration and then an increase in drug concentration with theinitiation of dexamethasone release from the polymer matrix (see FIG.1).

Initial mean vitreous humor dexamethasone concentrations at 3 and 6hours were lower for the tablet dosage form than the extruded dosageform at both dose levels. However, the tablet dosage form demonstratedhigher drug concentrations than the extruded dosage form at allremaining time points (12, 24 and 72 hours) at both dose levels.Overall, peak mean vitreous humor dexamethasone concentrations weresimilar between the two dosage forms at corresponding dose levels. Themean vitreous humor concentrations for the tablet dosage form withineach dose level did not change substantially over the 72-hour studyperiod. Peak mean vitreous humor concentrations of dexamethasone wereobserved at 24 hours for both the 350T and 700T groups (261.82 ng/mL and716.33 ng/mL, respectively) (FIG. 1).

The proportion of dexamethasone released from the DEX PS DDS over the72-hour study period for the extruded dose levels (350E and 700E) wasconsistent across both dose levels at approximately 15%. Likewise thetablet dosage form also had similar dexamethasone release profiles forboth dose levels (350T and 700T), but released a significantly greaterproportion of the total dexamethasone (approximately 35%) by the end ofthe 72-hour study (FIG. 2).

Consistent with the greater release of dexamethasone from the tabletdosage form during this 72-hour study, higher mean concentrations ofdrug were measured in the aqueous humor at all sampling points for boththe 350T and 700T groups when compared to the 350E and 700E groups. Ingeneral, for both dosage forms and dose levels, the mean aqueous humorconcentrations of dexamethasone were approximately 10 times lower thanthe mean vitreous humor concentrations of dexamethasone.

Plasma dexamethasone concentrations were observed at all sampling pointsfor the tablet dosage form, but only minimally above the limit ofquantification (1.00 ng/mL). Measurable dexamethasone concentrationswere not observed in the plasma of animals in the 350E group, and plasmaconcentrations were measurable, but at very low concentrations, for the700E group at 3, 6 and 12 hours.

With a single exception, mean dexamethasone concentrations were belowthe limit of quantification in the vitreous and aqueous humor of thecontrol eyes for both dosage forms at all dose levels. The exception wasobserved in the 350T dose control group in which a vitreous humorconcentration of 2.98 ng/mL was observed at 6 hours.

CONCLUSION

Although release profiles were similar among dose levels (350 μg and 700μg) within each dosage form, the extruded dosage form releasedapproximately 15% of the dose over the study period while the tabletdosage form released approximately 35% over the same period.

The results of this study demonstrate that peak mean vitreous humorconcentrations of dexamethasone are similar for the tablet and extrudeddosage forms over the 72-hour study period. For both dosage forms themean concentrations of dexamethasone observed in the vitreous humor,aqueous humor, and plasma were consistent with the dose levelsadministered.

Example 5 Comparison of Tablet and Extruded Dexamethasone BioerodibleVitreal Implants Over 84 Days

An 84 day experiment was carried out to compare the pharmacokinetics oftableted and extruded forms at two dose levels of DEX PS DDS® uponimplantation into the posterior segment (vitreous) of the eyes of NewZealand white rabbits.

This experiment was designed to evaluate the intraocular (vitreous andaqueous humor) and systemic (plasma) pharmacokinetics (PK) of two dosageforms of DEX PS DDS, tableted and extruded, with each dosage formevaluated at two dose levels. The same four test implant types used inExample 1 were used in this experiment: 350 μg extruded DEX PS DDS(350E), 700 μg extruded DEX PS DDS (700E), 350 μg tableted DEX PS DDS(350T) and 700 μg tableted DEX PS DDS (700T).

On Day 0, 312 male New Zealand White rabbits each received 1 of the 4test implants (78 rabbits per test article) in the posterior segment(vitreous) of the right eye. The left eye of each animal served as acontrol. Euthanasia and necropsy were performed at Days 1, 3, 7, 14, 21,28, 35, 45, 56, 70, and 86. Prior to euthanasia, plasma was collectedfor evaluation of plasma dexamethasone levels. Vitreous humor sampleswere collected at necropsy, and the vitreous was divided into twosections: the section containing the DEX PS DDS remnant(s) and theremaining vitreous humor section without DEX PS DDS remnants wereanalyzed.

The experiment was carried out in compliance with Good LaboratoryPractice (GLP Regulations, 21 CFR, Part 58). The section of the vitreoushumor containing the DEX PS DDS remnant(s) was analyzed fordexamethasone concentrations and vitreous humor and aqueous humor of thetreated eye were assayed for dexamethasone concentrations, as was thevitreous and the aqueous humor of the control eye, and the plasma. Asubset of twenty-four animals (6 per test implant) underwent weeklyophthalmic examinations to monitor the polymer matrix dissolution of thetest article and dissolution was evaluated in all animals with testarticle implants prior to euthanasia. Dissolution was evaluated by aveterinary ophthalmologist using a numerical grading scale.

No mortality occurred following implantation of the DEX PS DDS.Anesthesia and surgical recovery led to minor weight loss early in thestudy, however none of the animals necropsied after Day 45 demonstratedan overall weight loss between surgery and necropsy, indicating that anyearly weight loss was regained.

Vitreous humor concentrations of dexamethasone were observed in the 350Egroup on Day 1 (10.66 ng/mL) through Day 28 (6.99 ng/mL), with peak meanconcentrations at Day 14 (111.30 ng/mL) and Day 21 (105.10 ng/mL). Inthe 700E group, mean vitreous humor concentrations of dexamethasone weremeasured from Day 1 (52.63 ng/mL) through Day 28 (119.70 ng/mL), withpeak mean concentrations observed on Day 14 (435.60 ng/mL) and Day 21(527.50 ng/mL). By Day 35, mean concentrations of dexamethasone were ator below the limit of quantification (2.50 ng/mL) for both levels of theextruded dosage form (FIG. 3).

For the 350T group, peak mean dexamethasone concentrations in thevitreous humor were identified on Day 1 (142.20 ng/mL) and Day 3 (89.58ng/mL), with measurable concentrations observed through Day 56 (2.79ng/mL). For the 700T group, peak mean dexamethasone concentrations werealso observed at Day 1 (198.56 ng/mL) and Day 3 (193.06 ng/mL), withmeasurable concentrations observed intermittently through Day 86 (3.03ng/mL) (FIG. 3).

The percent of dexamethasone released for each dosage form at each doselevel was determined by assaying the section of the vitreous humorcontaining the DEX PS DDS remnants. Overall, the extruded dosage formprovided a more consistent release of dexamethasone as evidenced by thelower standard deviations over the sampling period. For both dosageforms and dose levels, the mean percent of dexamethasone released by Day35 was >90% (FIG. 4).

In the treated right eye, measurable concentrations of dexamethasonewere found in the aqueous humor for both dosage forms and both doselevels at most time points up to Day 28, with peak mean aqueous humorconcentrations paralleling peak mean vitreous humor concentrations.However, at most time points, peak mean plasma concentrations ofdexamethasone were below, at or slightly above the limit ofquantification (1.00 ng/mL). In the vitreous and aqueous humor of thecontrol eyes dexamethasone content was generally below the limit ofquantification.

Polymer matrix dissolution was evaluated in each group of animals atnecropsy. Complete dissolution of the polymer matrix was observed atapproximately 3 months in 58% of the animals receiving the extrudeddosage form, and in 17% of the animals receiving the tablet dosage form,suggesting improved polymer matrix dissolution for the extruded dosageform.

In a subset of 24 animals, polymer matrix dissolution was assessedweekly. For the extruded dosage form, significant dissolution (1-24%remaining) had occurred in all but one eye by Day 46. Similarly, for thetablet dosage form, significant dissolution had occurred in all eyes byDay 57. Complete polymer matrix dissolution was observed byapproximately 5 months for 67% of the extruded dosage form group and for58% of the tablet dosage form group.

In summary, both dosage forms released an equivalent dose ofdexamethasone, i.e., either 350 μg or 700 μg, over approximately 35days, but achieved peak concentrations at different time points duringthe release period. Gradual, less variable release of dexamethasone, andmore rapid dissolution of the polymer matrix were observed with theextruded dosage form.

Example 6 Extended Treatment of Macular Edema with an IntravitrealDexamethasone Implant

An experiment was carried out with a biodegradable drug delivery systemfor implanting into the vitreous of the eye and release of dexamethasone(referred to hereafter as a “DEX PS DDS”). Such an implant can be usedfor the treatment of ocular conditions, such as macular edema.

Implants made according to the methods of Examples 1 and 2 were used.These implants form an intravitreal drug delivery system, which can bereferred to as a Dexamethasone Posterior Segment Drug Delivery System(DEX PS DDS®), can deliver a 350 μg or 700 μg dose of dexamethasoneintravitreally over approximately 35 days, allowing for a lower totaldose and sustained drug levels to the target areas. DEX PS DDS iscomposed of dexamethasone homogeneously dispersed into a biodegradablematrix of copolymers of lactic acid and glycolic acid, PLGA (poly[lactic-glycolic] acid), a material commonly used in medical devicessuch as absorbable sutures. Dexamethasone is released gradually into theback of the eye over a period of approximately 35 days. The DEX PS DDSdoes not need to be removed since the copolymer dissolves completelyover time.

By effectively delivering a sustained release anti-inflammatory drugintravitreally, DEX PS DDS can offer patients and clinicians a valuablenew therapeutic option in the treatment of persistent macular edema thathas persisted despite intervention, while reducing the potential forside-effects typically observed from steroid administration throughother routes of delivery (e.g. systemic, etc.).

The objective of the experiment was to compare the safety and efficacyof two doses of DEX PS DDS (350 μg and 700 μg) versus observation (i.e.patients in which no implant was used) in the treatment of persistentmacular edema (PME) persisting at least 90 days after laser treatment orafter 90 days of medical management by a physician. Patients with PMEassociated with diabetic retinopathy, uveitis, retinal vein occlusion,and Irvine-Gass Syndrome were in the experiment.

A total of 306 patients, ages≧12 years old, with persistent macularedema associated with diabetic retinopathy, uveitis, branch retinal veinocclusion (BRVO), central retinal vein occlusion (CRVO) or Irvine-GassSyndrome, persisting for at least 90 days following treatment were partof this 180-day study. At baseline, each patient provided writteninformed consent and a complete medical history including ocular historyand prior medications (within the last 30 days). Potential studyparticipants underwent measurements of best-corrected visual acuity(BCVA) based on ETDRS and intraocular pressure (IOP), and were examinedfor clinical signs of anterior chamber cells, anterior chamber flare,anterior vitreous cells, cataract, vitreal haze/retinal obscuration,vitreous/retinal hemorrhage, retinal detachment/tear and macular edema.Patients also underwent fluorescein angiography, fundus photography, andoptical coherence tomography. Diabetic patients were tested for HbA_(1c)and pre-menopausal women underwent urine pregnancy testing. For thepurposes of this experiment persistent macular edema was defined asretinal thickening at the center of the fovea, visual acuity equal to orworse than 20/40, and angiographic evidence of leakage in the perifovealcapillary network.

After signing the informed consent form and determination ofeligibility, patients were randomly assigned to treatment with 350 μgDEX PS DDS, or 700 μg DEX PS DDS, or observation.

DEX PS DDS (350 μg or 700 μg dexamethasone) was surgically implanted inthe study eye of patients in the two active treatment groups. Insertionwas performed through an incision in the pars plana inferotemporally,unless contraindicated during surgery by the Investigator. Afterclosure, the suture knot was buried and subconjunctival and topicalantibiotics were used prophylactically. If the delivery system becamecontaminated or damaged prior to insertion, it was replaced with a new,sterile system.

Visual Acuity

The visual acuity of patients in this study was measured according tothe standard procedure developed for the Early Treatment DiabeticRetinopathy Study (ETDRS) and adapted for the Age-Related Eye DiseaseStudy Protocol (AREDS) and this study. Visual acuity testing wasrequired at a distance of 4-meters and, for subjects with sufficientlyreduced vision, at 1-meter. ETDRS Charts 1 and 2 were used for testingthe right and left eye, respectively, and Chart R was used forrefraction.

Contrast Sensitivity

Contrast sensitivity, the ability of the eye to discern subtle degreesof contrast and size, is a sensitive measure of visual function whichcan be affected by the presence of retinal disease. Contrast sensitivitytesting was performed as an additional measure of visual function usingstandardized, preprinted charts and standardized photopic and mesopicillumination by certified examiners. The outcome was measured as thelowest level of contrast at which a patient could distinguish patternsize displayed using a sine-wave contrast sensitivity vision test.

Fluorescein Angiography

Fluorescein angiography was conducted prior to randomization to provideangiographic evidence of leakage involving the perifoveal capillarynetworks and at select follow-up visits to assess anatomical improvementin macular edema. A central reading laboratory, FPRC (Fundus PhotographReading Center, Madison, Wis.), was used to perform all readings.Readers were masked to patient treatment assignments.

Fundus Photography

Fundus photography was performed to assess macular thickness, ananatomical measure of macular edema, using standard techniques bycertified photographers at each site. The photographs were assessed bymasked readers at a central reading laboratory (FPRC).

Optical Coherence Tomography

Optical coherence tomography (OCT) is a laser-based non-invasive,diagnostic system providing high-resolution images of the retina (10μm). Macular thickness, an anatomical indicator of macular edema, wasassessed by a central reading laboratory (FPRC) from images obtained atBaseline and select follow-up visits. Readers were masked to patienttreatment assignments.

Schedule of Exams

Patients, including both treatment groups and the observation group,were assessed according to the following schedule:

-   -   BCVA by ETDRS (Baseline, Days 7, 30, 60, 90, 180 or Early        Termination);    -   Contrast sensitivity (Baseline, Days 30, 60, 90 or Early        Termination);    -   Intraocular pressure (Baseline, Days 1, 7, 30, 60, 90, 180 or        Early Termination);    -   Slit lamp biomicroscopy with fundus contact lens (Baseline, Days        1, 7, 30, 60, 90 or Early Termination) for clinical signs of        macular edema;    -   Slit lamp assessment (Baseline, Days 1, 7, 30, 60, 90, 180 or        Early Termination) for anterior chamber cells, anterior chamber        flare, anterior vitreous cells, and cataract(s);    -   Indirect ophthalmoscopy (Baseline, Days 1, 7, 30, 60, 90, 180 or        Early Termination) for vitreal haze/retinal obscuration,        vitreous/retinal hemorrhage, retinal detachment/tear. DEX PS DDS        was observed on Days 30, 60, 90, 180 or Early Termination only        (with scleral depression);    -   Fluorescein angiography (Baseline, Days 30, 90 or Early        Termination);    -   Fundus photography (Baseline, Day 0 [DEX PS DDS-treated group        only if deemed necessary] Day 1 [Observation Group only if        deemed necessary], Days 30, 60, 90 or Early Termination);    -   Optical coherence tomography (OCT) for macular thickness        quantification at clinical sites where test available (Baseline,        Days 30, 90 or Early Termination);    -   Vital signs: blood pressure (Baseline, Days 1, 7, 30, 60, 90);    -   HbA_(1c)—Baseline, Days 30, 60, 90 or Early Termination (if        diabetic).

Efficacy

The primary efficacy parameter was BCVA (by ETDRS) improvement at theDay 90 follow-up visit. The BCVA improvement rate was defined as theproportion of subjects who had 2 lines or more improvement frombaseline.

Secondary efficacy parameters were:

-   -   BCVA improvement at the Day 30 and Day 60 follow-up visits from        baseline;    -   Mean change in the BCVA in LogMAR (log of the minimum angle of        resolution) at the Day 30, Day 60, and Day 90 follow-up visits        from baseline;    -   Mean change in measurements based on the contrast sensitivity        evaluation performed at the Day 30, Day 60 and Day 90 follow-up        visits from baseline;    -   Mean change in measurements based on the fluorescein angiography        evaluation performed at the Day 30 and Day 90 follow-up visits;    -   Mean change in measurements based on the fundus photography        evaluation performed at the Day 30, Day 60 and Day 90 follow-up        visits;    -   Mean change in the retinal thickness in 1-mm diameter center        subfield based on the OCT evaluation at the Day 30 and Day 90        follow-up visits from baseline;    -   Mean change in measurements based on the clinical signs of        persistent macular edema (PME) evaluation by slit lamp        biomicroscopy performed at the Day 1, Day 7, Day 30, Day 60 and        Day 90 follow-up visits;    -   Mean change in BCVA from Baseline to the Day 7, 30, Day 60 and        Day 90 follow-up visits.

Results

A total of 315 patients with persistent macular edema (PME) wereenrolled in the clinical study. One hundred five (105) patients wereassigned to each of the three study groups, i.e., DEX PS DDS 350 μg, DEXPS DDS 700 μg, or observation only. Five patients assigned to the 350 μgtreatment group and 4 patients assigned to the 700 μg treatment groupwithdrew before DEX PS DDS treatment was initiated due to a change ineligibility status since randomization or personal reasons and thereforewere not included within the intent-to-treat population. Of the totalintent-to-treat (ITT) study population (n=306), 51.3% of the patientswere male and 48.7% were female, with 9 patients less than 40 years ofage (2.9%), 119 patients in the 40 to 65 year range (38.9%), and 178patients over 65 years of age (58.2%). The mean age was 66 years(SD=11.9) consistent with the greater prevalence of eye pathologiesamong older adults. The majority of patients were Caucasian (77.8%),with the remaining patients from the following ethnic groups: Black(7.5%), Hispanic (11.1%), Asian (2.6%), and Native American (1.0%).

Improved Visual Acuity

As shown in Table 1, use of both the 350 μg and the 700 μg DEX PS DDSresulted in visual acuity improvement of two or more lines in BCVA atDay 30, Day 90 and as well at Day 180. All the visual acuity improvementpercentages shown in Table 1 were greater at each time (Day 90 and Day180) and for each type of implant (350 μg and 700 μg) than was thevisual acuity improvement percentage seen in the patients in theobservation group.

Thus, it was demonstrated that use of an implant according to the methodset forth herein permits a patients' visual acuity to improve and thatthe patient's improved visual acuity can be retained for a period oftime long after the implant has released all the dexamethasone.

TABLE 1 Improved Visual Acuity 30, 60 and 90 Days after Placement ofIntravitreal Implant DEX PS DDS DEX PS DDS Observation 350 mg 700 mggroup (n = 100) (n = 101) (n = 105) Day 30 BCVA n 89 93  94 ≧2 line gain21% 22% 16%  ≧3 line gain  9% 13% 6% Day 90 BCVA n 92 98 100 ≧2 linegain 26% 37% 19%  ≧3 line gain 13% 16% 9% Day 180 BCVA n 92 98 100 ≧2line gain 27% 36.%  19%  ≧3 line gain 13% 19% 8%

Improved Visual Contrast Sensitivity

Change in contrast sensitivity, an assessment of visual function, wasmeasured at baseline, and at Days 30, 60, and 90 using a sine-wavecontrast sensitivity vision test. As shown by Table 2, the LOCF meanContrast Sensitivity Score at 1.5 cpd (Patch A) was higher in patientsin both DEX PS DDS treatment groups compared to the observation group atDay 60 (p<0.001) and Day 90 (p=0.006). The improvement appeared firstamong those in the 350 μg treatment group at Day 30 (p=0.028), but byDay 60 patients in both the 350 μg and the 700 μg treatment groupsexperienced significant visual function improvement (p<0.001 andp=0.011, respectively). This improvement was maintained to Day (p=0.004and p=0.010, respectively). A similar treatment effect (data not shown)on LOCF mean Contrast Sensitivity Score at 3.0 cpd (Patch B) wasobserved for both the 350 μg and the 700 μg DEX PS DDS treatment groups,compared to the observation group, by Day 60 (p<0.001 and p=0.030,respectively), and continued through Day 90 for both treatment groups(p=0.021 and p=0.007, respectively).

Thus, it was demonstrated that use of an implant according to the methodset forth herein permits a patients' visual contrast sensitivity toimprove and that the patient's improved visual contrast sensitivity canbe retained for a period of time long after the implant has released allthe dexamethasone.

TABLE 2 Improved Visual Contrast Sensitivity 30 Days, 60 Days and 90Days after Placement of Intravitreal Implant Treatment Group DEX PS DDSDEX PS DDS Observation 350 mg 700 mg Group Change from 0.89 0.56 0.38Baseline at Day 30 Change from 1.21 0.80 0.13 Baseline at Day 60 Changefrom 1.02 0.97 0.33 Baseline at Day 90

Improved (Decreased) Retinal Thickness (OCT)

Change in retinal thickness, an anatomical measure of macular edema, wasassessed by Optical Coherence Tomography (OCT) at Days 30 and 90.Patients who had baseline and at least one follow-up evaluation wereincluded in this analysis. As shown by Table 3, the LOCF average retinalthickness score was improved by Day 30 for both treatment groups ascompared to the observation group (p<0.001 for 350 μg and 700 μg DEX PSDDS). This improvement continued to Day 90 for both treatment groups,with a significantly greater decrease in retinal thickness in the 700 μgtreatment group (p<0.001) and the 350 μg treatment group (p=0.016)compared to the observation group.

Thus, it was demonstrated that use of an implant according to the methodset forth herein permits a patients' aberrant retinal thickness toimprove and that the patient's improved (decreased) retinal thicknesscan be retained for a period of time long after the implant has releasedall the dexamethasone.

TABLE 3 Improved (Decreased) Retinal Thickness as Measured by OpticalCoherence Tomography (OCT) 30 Days and 90 Days after Placement ofIntravitreal Implant Treatment Group Retinal Thickness DEX PS DDS DEX PSDDS Observation (μm) 350 mg 700 mg Group Change from Baseline −102.96−157.11 12.73 at Day 30 Change from Baseline −63.08 −147.20 9.54 at Day90

Improved (Decreased) Retinal Vessel Leakage

Categorical improvement in leakage of the retinal vasculature, ananatomical measure of macular edema, was assessed by fluoresceinangiography at baseline, Day 30 and at Day 90. Patients who had baselineand at least one follow-up evaluation were included in the analysis. Asshown by Table 4, LOCF fluorescein leakage scores improved as comparedto the observation group for patients in both treatment groups by Day30., By Day 90, fluorescein leakage for both DEX PS DDS treatment groupswas significantly improved over the observation group (700 μg; p<0.001and 350 mg; p=0.001).

Thus, it was demonstrated that use of an implant according to the methodset forth herein permits a patients' retinal blood vessel leakage todecrease and that this improvement can be retained for a period of timelong after the implant has released all the dexamethasone.

TABLE 4 Improved (Decreased) Retinal Blood Vessel Leakage as Measured byFluorescein Angiography 30 Days and 90 Days after Placement ofIntravitreal Implant Improvement in Treatment Group Maximum DEX PS DDSDEX PS DDS Observation Fluorescein Leakage 350 mg 700 mg Group Changefrom Baseline at Day 30 ≧2 levels better 17% 28% 6% ≧3 levels better 11%22% 4% Change from Baseline to Day 90 ≧2 levels better 20% 34% 4% ≧3levels better 16% 25% 1%

Improved (Decreased) Retinal Thickness (Fundus Photography)

Categorical improvement in retinal thickness was also assessed by fundusphotography at baseline, Day 30 and at Day 90. Patients who had baselineand at least one follow-up evaluation were included in the analysis. Asshown by Table 5, at Day 30, retinal thickness scores for both DEX PSDDS treatment groups were significantly improved over the observationgroup (700 μg; p<0.001 and 350 mg; p=0.031) By Day 90, the 700 μgtreatment group continued to show statistical significance inimprovement of LOCF retinal thickness scores (p<0.001).

Thus, it was demonstrated that use of an implant according to the methodset forth herein permits a patients' aberrant retinal thickness toimprove and that the patient's improved (decreased) retinal thicknesscan be retained for a period of time long after the implant has releasedall the dexamethasone.

TABLE 5 Improved (Decreased) Retinal Thickness as Measured by FundusPhotography 30 Days and 90 Days after Placement of Intravitreal ImplantTreatment Group Improved Retinal DEX PS DDS DEX PS DDS ObservationThickness 350 mg 700 mg Group Change from Baseline at Day 30 ≧2 levelsbetter 13% 23% 2% ≧3 levels better  6% 14% 1% Change from Baseline atDay 90 ≧2 levels better 16% 30% 4% ≧3 levels better 10% 24% 2%

Intraocular Pressure

Intraocular pressure (IOP) was recorded on days 1, 7, 30, 60, 90 and the180. Over the course of the study 22 events of elevation in IOP≧25 mm Hgwere noted in 17 patients receiving the 350 μg treatment and 22 eventsin 15 patients receiving the 700 μg treatment. No event of elevation inIOP≧25 mmHg was noted in the observation group. Differences in IOP of≧25 mm Hg between the 700 μg treatment group (n=7) and the observationgroup were significant at the day 180 visit only (p=0.014). Nostatistical difference was seen at any time interval for the 350 μgtreatment group as compared to the observation group.

Of the 7 patients with elevated IOP at day 180, one patient had anocular history of glaucoma in both eyes at the baseline visit. A secondpatient did not receive medication and the elevated IOP resolved thesame day.

As shown by Table 6, increases of IOP 10 mm Hg from baseline occurred ina small number of eyes in all three groups. At no time was there astatistical difference between the 350 μg group and the observationgroup. When the 700 μg treatment group was compared to the observationgroup, statistical difference was seen at Day 60 only (p=0.044).

Prior to the present invention is was believed that intravitrealadministration of a steroid would cause a much more significant increasein intraocular pressure than was observed in the present study. See e.g.Wingate R., et al., Intravitreal triamcinolone and elevated intraocularpressure, Aust & New Zea. J of Ophthalmology 27(6):431-2, December 1999;Gillies M., et al., Safety of an intravitreal injection oftriamcinolone, Arch Ophthalmol vol 122, 336-340 March 2004, and; JonasJ. et al., Intraocular pressure after intravitreal injection oftriamcinolone acetonide, Br. J. Ophthalmol 2003; 87: 24-27

TABLE 6 Summary of Change from Baseline to Follow-up Visits inIntraocular Pressure ≧10 mmHg Follow-up Visit Study Day Day Day GroupDay 1 7 Day 30 Day 60 90 180 DEX PS % of 5 2 2 2 2 2 DDS patients with350 mg Increase in IOP over baseline of >=10 mm Hg DEX PS % of 5 3 1 3 26 DDS patients 700 mg with Increase in IOP over baseline of >=10 mm HgObservation % of 3 4 2 0 1 1 Group patients with Increase in IOP overbaseline of >=10 mm Hg

Cataract Development

There was no significant difference in cataract development betweentreatment groups at any time point. Over 60% of patients in all threestudy groups had a cataract present at baseline. As shown by Table 7there was no significant new cases of cataract.

TABLE 7 New Cases of Cataract Observed During the Study Number of NewCataracts by Type of Cataract Treatment Group Cortical NuclearSubcapsular 350 mg DEX PS DDS (n = 100) 0 1 0 700 mg DEX PS DDS (n =101) 1 1 1 Observation Group (n = 105) 1 1 1

Prior to the present invention is was believed that intravitrealadministration of a steroid would cause a much more significant increasein cataracts than was observed in the present study. See e.g. GilliesM., et al., Safety of an intravitreal injection of triamcinolone, ArchOphthalmol vol 122, 336-340 March 2004.

Implant Dissolution and Location

DEX PS DDS dissolution and location were monitored by slit lampexamination at all visits over the course of the study. DDS dissolutionwas quantified based on a scale of absent, trace present, <25%, <50%,≦100% or >100% present. No differences were observed between thedissolution rate of the 350 μg and the 700 μg treatment groups. At theDay 180 visit, 68.1% of patients in the 350 μg group and 65.3% ofpatients in the 700 mg group had no visible presence of residual DEX PSDDS. Of the remaining patients, most had only trace to ≦25% amounts ofresidual DEX PS DDS remaining by the Day 180 visit. There was nosignificant difference in the location of the DEX PS DDS between the twotreatment groups at any time during the course of the study.

The DEX PS DDS was found to be stable upon placement. No significantmigration of the DEX PS DDS was noted for either the 350 μg or 700 μgtreatment group. Categorical analysis across all DEX PS DDS locationsshowed no significant difference at any time interval using Fisher'sExact test.

To conclude the safety and efficacy of two doses of DexamethasonePosterior Segment Drug Delivery System (DEX PS DDS) versus observationfor the treatment of persistent macular edema (PME) was tested in aPhase 2, prospective, randomized, multicenter, dose-ranging, controlledclinical trial. A total of 315 patients, ≧15 years of age, with PMEassociated with diabetic retinopathy, uveitis, branch retinal veinocclusion (BRVO), central retinal vein occlusion (CRVO) or Irvine-GassSyndrome present for at least 90 days despite prior intervention wereenrolled in this 180-day study. Patients were randomized in a 1:1:1ratio to one of three study groups: 700 μg DEX PS DDS, 350 μg DEX PS DDSor observation. The intent-to-treat (ITT) population consisted of 306patients who were balanced between the three study groups in terms ofpatient sex, age, race, baseline etiology and duration of initial onsetand duration of persistent macular edema.

Example 7 Extended Treatment of Ocular Conditions with Various ActiveAgents

An implant can be formulated with various active agents following theprocedures in Examples 1 and 2. These implants can provide an extendedtherapeutic treatment of an ocular condition, that is a therapeuticaffect during a period of time after release of all of the active agentfrom the implant and during which there is no longer a therapeuticamount of the active agent present at the ocular site at which theimplant was placed. Thus, an implant can be prepared containing anonsteroidal anti-inflammatory agent, such as ketoralac (available fromAllergan, Irvine, Calif. as ketoralac tromethamine ophthalmic solution,under the tradename Acular). Thus, for example, a ketoralac extendedtherapeutic treatment implant can be implanted into an ocular site (i.e.into the vitreous) of a patient with an ocular condition for a desiredextended therapeutic effect. The ocular condition can be an inflammatorycondition such as uveitis or the patient can be afflicted with one ormore of the following afflictions: macular degeneration (includingnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (including cystoid macular edema anddiabetic macular edema); Behcet's disease, diabetic retinopathy(including proliferative diabetic retinopathy); retinal arterialocclusive disease; central retinal vein occlusion; uveitic retinaldisease; retinal detachment; retinopathy; an epiretinal membranedisorder; branch retinal vein occlusion; anterior ischemic opticneuropathy; non-retinopathy diabetic retinal dysfunction, retinitispigmentosa and glaucoma. The implant(s) can be inserted into thevitreous using the procedure such as trocar implantation. The implantcan release a therapeutic amount of the active agent to provide andretain a therapeutic effect for an extended period of time to therebytreat a symptom of an ocular condition.

Such an implant to provide an extended therapeutic treatment of anocular condition can also be prepared containing a steroid, such ananti-angiogenesis steroid, such as an anecortave, as the active agent.

VEGF (Vascular Endothelial Growth Factor) (also known as VEGF-A) is agrowth factor which can stimulate vascular endothelial cell growth,survival, and proliferation. VEGF is believed to play a central role inthe development of new blood vessels (angiogenesis) and the survival ofimmature blood vessels (vascular maintenance). Tumor expression of VEGFcan lead to the development and maintenance of a vascular network, whichpromotes tumor growth and metastasis. Thus, increased VEGF expressioncorrelates with poor prognosis in many tumor types. Inhibition of VEGFcan be an anticancer therapy used alone or to complement currenttherapeutic modalities (eg, radiation, chemotherapy, targeted biologictherapies).

VEGF is believed to exert its effects by binding to and activating twostructurally related membrane receptor tyrosine kinases, VEGF receptor-1(VEGFR-1 or flt-1) and VEGFR-2 (flk-1 or KDR), which are expressed byendothelial cells within the blood vessel wall. VEGF may also interactwith the structurally distinct receptor neuropilin-1. Binding of VEGF tothese receptors initiates a signaling cascade, resulting in effects ongene expression and cell survival, proliferation, and migration. VEGF isa member of a family of structurally related proteins (see Table Abelow). These proteins bind to a family of VEGFRs (VEGF receptors),thereby stimulating various biologic processes. Placental growth factor(PlGF) and VEGF-B bind primarily to VEGFR-1. PlGF modulates angiogenesisand may also play a role in the inflammatory response. VEGF-C and VEGF-Dbind primarily to VEGFR-3 and stimulate lymphangiogenesis rather thanangiogenesis.

TABLE A VEGF Family Members Receptors Functions VEGF (VEGF-A) VEGFR-1,VEGFR-2, Angiogenesis Vascular neuropilin-1 maintenance VEGF-B VEGFR-1Not established VEGF-C VEGF-R, VEGFR-3 Lymphangiogenesis VEGF-D VEGFR-2,VEGFR-3 Lymphangiogenesis VEGF-E (viral VEGFR-2 Angiogenesis factor)PIGF VEGFR-1, neuropilin-1 Angiogenesis and inflammation

An extended therapeutic effect implant system to treat an ocularcondition can contain as active agent a compound with acts to inhibitformation of VEGF or to inhibit the binding of VEGF to its VERFR. Theactive agent can be, for example, ranibizumab (rhuFab V2) (Genentech,South San Francisco, Calif.) and the implant(s) can be made using themethod of Example 1 or the method of Example 2, but with use ofranibizumab as the active agent, instead of dexamethasone. Ranibizumabis an anti-VEGF (vascular endothelial growth factor) product which mayhave particular utility for patients with macular degeneration,including the wet form of age-related macular degeneration. The implantcan be loaded with about 100-300 μg of the ranibizumab

Pegaptanib is an aptamer that can selectively bind to and neutralizeVEGF and may have utility for treatment of, for example, age-relatedmacular degeneration and diabetic macular edema by inhibiting abnormalblood vessel growth and by stabilizing or reverse blood vessel leakagein the back of the eye resulting in improved vision. An extendedtherapeutic treatment implant can be made with of pegaptanib sodium(Macugen; Pfizer Inc, New York or Eyetech Pharmaceuticals, New York) asthe active agent by loading about 1 mg to 3 mg of Macugen according tothe Example 1 or 2 method.

The pegaptanib sodium extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired extended therapeutic effect.

An extended treatment bioerodible intraocular implant for treating anocular condition, such as an ocular tumor can also be made as set forthin this Example using about 1 mg of the VEGF Trap compound availablefrom Regeneron, Tarrytown, new York.

An extended therapeutic treatment implant treat an ocular condition cancontain a beta-adrenergic receptor antagonist (i.e. a “beta blocker)such as levobunolol, betaxolol, carteolol, timolol hemihydrate andtimolol. Timolol maleate is commonly used to treat of open-angleglaucoma. Thus, an extended therapeutic treatment bioerodible implantcontaining timolol maleate (available from multiple different suppliersunder the trade names Timoptic, Timopol or Loptomit) as the active agentcan be made using the method of Example 1 or the method of Example 2,but with use of timolol maleate instead of dexamethasone. Thus, about 50μg of the timolol maleate can be loaded into each of the three implantsprepared according to the Example 1 or method.

The timolol extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired extended therapeutic effect. The ocularcondition can be an inflammatory condition such as uveitis or thepatient can be afflicted with one or more of the following afflictions:macular degeneration (including non-exudative age related maculardegeneration and exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma.

An extended therapeutic treatment implant system can be used to treat anocular condition can contain a prostamide. Prostamides are naturallyoccurring substances biosynthesized from anandamide in a pathway thatincludes COX2. Bimatoprost (Lumigan) is a synthetic prostamide analogchemically related to prostamide F. Lumigan has been approved by the FDAfor the reduction of elevated intraocular pressure (IOP) in patientswith open-angle glaucoma or ocular hypertension who are intolerant of orinsufficiently responsive to other IOP-lowering medications. Lumigan isbelieved to lower intraocular pressure by increasing the outflow ofaqueous humor.

Thus, an extended therapeutic treatment bioerodible implant containingLumigan (Allergan, Irvine, Calif.) as the active agent can be made usingthe method of Example 1 or the method of Example 2, but with use ofLumigan instead of dexamethasone. Thus, about 100 μg of Lumigan can beloaded into each of the three implants prepared according to the Example1 or 2 method.

The Lumigan extended therapeutic effect implant an be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma.

An extended therapeutic treatment implant an be used to treat an ocularcondition wherein the implant contains as the active agent an alpha-2adrenergic receptor agonist, such as clonidine, apraclonidine, orbrimonidine. Thus, an extended release bioerodible implant systemcontaining brimonidine (Allergan, Irvine, Calif., as Alphagan orAlphagan P) as the active agent can be made using the method of Example1 or the method of Example 2, but with use of Alphagan instead ofdexamethasone. Thus, about 50 μg of Alphagan can be loaded into animplant prepared according to the Example 1 or 2 method.

The brimonidine extended therapeutic treatment implant can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect. The ocularcondition can be an inflammatory condition such as uveitis or thepatient can be afflicted with one or more of the following afflictions:macular degeneration (including non-exudative age related maculardegeneration and exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma.

An extended therapeutic effect implant used to treat an ocular conditioncan contain a retinoid such as an ethyl nicotinate, such as atazarotene. Thus, an extended release bioerodible implant systemcontaining tazarotene (Allergan, Irvine, Calif.) as the active agent canbe made using the method of Example 1 or the method of Example 2, butwith use of tazarotene instead of dexamethasone. Thus, about 100 μg to300 μg of tazarotene can be loaded into each of the three implantsprepared according to the Example 1 or 2 method.

The tazarotene extended therapeutic treatment implant can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect.

Generally, tyrosine kinase inhibitors are small molecule inhibitors ofgrowth factor signaling. Protein tyrosine kinases (PTKs) comprise alarge and diverse class of proteins having enzymatic activity. The PTKsplay an important role in the control of cell growth anddifferentiation. For example, receptor tyrosine kinase mediated signaltransduction is initiated by extracellular interaction with a specificgrowth factor (ligand), followed by receptor dimerization, transientstimulation of the intrinsic protein tyrosine kinase activity andphosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolichomeostasis, and responses to the extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates which have a catalytic domain; and (2)substrates which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). The RTKs comprise a large family of transmembranereceptors with diverse biological activities. The intrinsic function ofRTKs is activated upon ligand binding, which results in phosphorylationof the receptor and multiple cellular substrates, and subsequently in avariety of cellular responses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, theSrc subfamily of non-receptor tyrosine kinases is comprised of thelargest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. A more detailed discussion of non-receptor tyrosine kinasesis provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporatedherein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligands (U.S.Pat. No. 4,966,849), soluble receptors and antibodies (PCT ApplicationNo. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci. 90:10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek,et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell4:358 A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, etal, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors(PCT Application Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO94/14808; U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am.Assoc. Cancer Res. 35: 2268).

An extended therapeutic treatment implant to treat an ocular conditioncan contain a tyrosine kinase inhibitor (TKI) such as a TKI set forth inpublished U.S. patent application 2004 00019098 (available fromAllergan, Irvine, Calif.) as the active agent can be made using themethod of Example 1 or the method of Example 2, but with use of a TKIinstead of dexamethasone. Thus, about 100 μg of a TKI can be loaded intoeach of the three implants prepared according to the Example 1 or 2method.

The TKI extended therapeutic effect implant an be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired extended therapeutic effect.

It is believed that overstimulation of the N-methyl-D-aspartate (NMDA)receptor by glutamate is implicated in a variety of disorders. Memantineis an NMDA antagonist which can be used to reduce neuronal damagemediated by the NMDA receptor complex. Memantine is a available formMerz Pharmaceuticals, Greensboro, N.C. under the trade name Axura. Anextended release implant system can be used to treat an ocularcondition. The implant can contain an NMDA antagonist such as memantine.Thus, an extended therapeutic treatment bioerodible implant containingmemantine as the active agent can be made using the method of Example 1or the method of Example 2, but with use of memantine instead ofdexamethasone. Thus, about 400 μg of memantine can be loaded into eachof the three implants prepared according to the Example 1 or 2 method.

The memantine extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired extended therapeutic effect.

Certain estratropones have anti-angiogenesis, anti-neoplastic andrelated useful therapeutic activities. An extended therapeutic treatmentimplant can contain an estratropone such as 2-methoxyestradiol(available form Entremed, Inc., of Rockville, Md. under the tradenamePanzem). Thus, an extended therapeutic treatment bioerodible implantcontaining memantine as the active agent can be made using the method ofExample 1 or the method of Example 2, but with use of 2-methoxyestradiolinstead of dexamethasone. 2-methoxyestradiol can be used as a smallmolecule angiogenic inhibitor to block abnormal blood vessel formationin the back of the eye. Thus, about 400 μg of 2-methoxyestradiol can beloaded into each of the three implants prepared according to the Example1 or 2 method.

The 2-methoxyestradiol extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired extended therapeutic effect.

Using the same methodology set forth in Examples 1 and 2, additionalextended therapeutic treatment implants can be prepared wherein theactive agent is, for example, an agent to treat intravitreal hemorrhage(such as Vitrase, available from Ista Pharmaceuticals), an antibiotic(such as cyclosporine, or gatifloxacin, the former being available fromAllergan, Irvine, Calif. under the tradename Restasis and the later fromAllergan under the tradename Zymar), ofloxacin, an androgen, epinastine(Elestat, Allergan, Irvine, Calif.), or with a combination of two ormore active agents (such as a combination in a single extended releaseimplant of a prostamide (i.e. brimatoprost) and a best blocker (i.e.timolol) or a combination of an alpha 2 adrenergic agonist (i.e.brimonidine) and a beta blocker, such as timolol) in the same extendeddelivery system. A method using an implant within the scope of thepresent invention can be used in conjunction with a photodynamic therapyor laser procedure upon an eye tissue.

Example 8 Remnant Effect of DEX-PS-DDS on VEGF-Induced Retinopathy inMonkeys

Six cynomolgus monkeys, each weighing between 3-4.5 kg, were used forthese studies. Animals were maintained under anesthesia during allprocedures. Briefly, monkeys were first sedated with 10 mg/kg ketamine,administered intramuscularly and removed from their cage. Animals wereintubated with an appropriately sized and sealed endotracheal tube,immobilized with intraveneous administration of 0.45 mg/kg Zemuron®(rocuronium bromide, a neuromuscular blocking agent) and placed on aventilation-assist device (Engler 1000) with 100% oxygen gas.

The animals' pupils were dilated with 1 drop of 2.5% phenylephrine and 1drop of 1% tropicamide. End tidal CO₂, SpO₂ and heart rate were recordedat 10-minute intervals to monitor ventilation efficiency and ensurestability of the animal's physiological status. If necessary during thecourse of the experiment, a supplemental dose of 0.15 mg/kg Zemuron® wasadministered to maintain and insure the immobility of the animal.

Corneal hydration was maintained by ensuring that the eyelids remainedclosed when no imaging was being performed; during imaging procedures aspeculum was used to prop the eyelids of the sampled eye open and thecornea regularly bathed with 0.9% physiological saline. The eyelidspeculum was removed immediately following conclusion of imagingprocedures and the eyelids manually closed.

Animal recovery following conclusion of the endpoint measurements wascarefully monitored. The time from first eyelid movement to theambulatory state typically ranges from 20 minutes to 1 hour. Althoughintravenous administration of 0.022 mg/kg atropine and 0.045 mg/kgNeostigmine (an anticholinesterase agent) reduces recovery time to lessthan 10 minutes, it is preferable and may be safer to the animals' wellbeing to allow them to recover without drug intervention.

Animals were separated into two groups of three, one group receiving a700 μg intravitreal dexamethasone implant (DEX-PS-DDS) administered viathe infero-temporal pars plana region using a 22-gauge applicator intothe left (OS) eye, and the other group treated with an injection ofPS-DDS lacking dexamethasone, OS. Generally, all significantdexamethasone is released from the DDS implant within approximately 30days.

At 1 week, 7 weeks and 15 weeks post-injection, 1.25 μg human vascularendothelial growth factor isoform 165 (VEGF h165) in a volume of 50 μlwas injected OS with a 30-gauge needle 1-2 mm over the macula in bothcontrol and test groups in order to induce retinal changes such as thoseseen in conditions including macular degeneration and diabeticretinopathy.

Assessments of the following parameters were made pre-DEX-PS-DDS (orcontrol) injection, before treatment with VEGF, and 7 days after eachVEGF injection.

Seven days after each VEGF injection the following assessments weremade:

-   -   a) measurement of anterior chamber flare (0-4 scale using slit        lamp),    -   b) retinal vascular leak and dilation (0-3 scale using        fluorescein angiograms),    -   c) foveal thickness (using Zeiss® Optical Coherence Tomography),    -   d) optic nerve cup volume (using Heidelberg Retinal Tomography)        and    -   e) ERG (electroretinography) (using Espion® ColorDome®;        electrophysiology system).

The results of this experiment showed that Dex-PS-DDS inhibited thedevelopment of VEGF-induced retinopathy throughout the 16-weekexperiment. Signs of disease, including anterior chamber flare, vasculardilation, and leakage of blood into the retina were consistentlyobserved in the control group at the 2, and 16 week timepoints but wereabsent in the Dex-PS-DDS treated animals throughout the time period ofthe experiment.

Optic nerve head swelling in response to VEGF treatment in the controlgroup caused a decrease in cup volume to approximately 15%-18% of thecontrol eye; the cup volumes in the Dex DDS group at 2, 8 and 16 weekswere better preserved, having a cup volume of 64% (±15%), 75% (±4%) and96% (±12%), that of the control eye at 2, 8, and 16 weeks, respectively.

The VEGF-induced foveal thickness was consistently greater in thecontrol group: 150±9 μm, 462±181 μm, 968±270 μm at the 2, 8 and 16 weektimepoints, respectively. Foveal thickness remained unchanged over timein the Dex-PS-DDS group, within a range of 133-137 μm out to 4 months.

VEGF injection resulting in reduced ERG amplitude over the course of thestudy in both groups, indicating somewhat reduced retinal function;however, the reductions were 2 to 5-fold less in the Dex-PS-DDS animals.In the control group, % of OS responses for b-wave at 1 cd·s/m² was 52%(±5%), 32% (±15%) and 10% (±10%) at the 2, 8 and 16 week timepoints,respectively. By contrast, in the Dex-PS-DDS group, the correspondingvalues were 103% (±3%), 87% (±13%), and 51% (±10%).

These results indicate that dexamethasone, intravitreally administeredin a DDS device, can provide a therapeutic effect countering orresisting the at least one symptom of VEGF-induced retinopathy for asignificant time after the dexamethasone has been released from the DDSimplant. In a preferred embodiment the glucocorticoid has such acountering or resisting effect for at least 4 days following the releaseof all significant amounts of dexamethasone into the vitreous. In otherembodiments the glucocorticoid has such a countering or resisting effectfor at least 1 week, or at least 2 weeks, or at least 3 weeks, or atleast 4 weeks, or at least 5 weeks, or at least 6 weeks, or at least 7weeks, or at least 8 weeks, or at least 9 weeks, or at least 9 weeks, orat least 10 weeks, or at least 11 weeks, or at least 12 weeks followingthe release of all significant amounts of dexamethasone into thevitreous.

In another embodiment the present invention comprises a method ofpreventing the presentation of at least one symptom of a retinaldisorder comprising administering to the vitreous of a mammal at risk ofsuch presentation a glucocorticoid at a dosage effective to reduce theseverity of such symptom in a different patient suffering from saidretinal disorder, comprising administering said dosage to the vitreousof a patient's eye before the presentation of said at least one symptom.

Example 9 Remnant Effect after Intravitreal Invention of TriamcinoloneAcetonide (TA)

An experiment was carried out which determined existence of a remnanteffect (i.e. a therapeutic effect of the active agent when a therapeuticamount of the active agent was not longer present) of intravitealtriamcinolone. Six Dutch-belted rabbits were divided into two groups ofthree each. After standard pars plana vitrectomy, one group received 4mg of the glucocorticoid triamcinolone acetonide (TA) in a 0.1 ml volume(Kenalog® 40), and the other group received 0.1 ml of a 5% PLGA (polylactic/glycolic acid) solution. One minute later the TA or PLGA wasremoved with a subtotal vitrectomy and soft tip needle. Forty-eighthours after the surgery VEGF₁₆₅ (500 ng/50 μl) was injectedintravitreally via a 29 gauge needle to induce retinal vasculopathy andassess a pharmacological action of any remnant effect of either TA orPLGA. Assessment of retinal color fundus imaging, fluoresceinangiography (FA), and fluorometry was made upon VEGF administration and48 hours following such administration to assess leak from the retinavasculature as a result of VEGF₁₆₅ administration, and the effect ofeither TA or PLGA on such leakage.

Less leakage was seen in the TA-treated group than in the PLGA groupafter 48 hours upon fluorescence angiography. Fluorophotometry “areaunder the curve” analysis showed a change from baseline of 3±65% in theTA group and 487±260% in the PLGA group. Thus, TA shows residualpharmacological activity 4 days following the procedure, i.e. a remnanteffect.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

What is claimed is:
 1. An ocular implant for treating an ocularcondition comprising an active agent and a carrier associated with theactive agent, wherein the carrier comprises a 30/10 w/w mixture ofhydrophilic end PLGA and hydrophobic end PLGA and wherein the activeagent is a prostamide and wherein the ocular implant is formed by anextrusion method.
 2. The ocular implant of claim 1, wherein theprostamide is bimatoprost.
 3. The ocular implant of claim 1, wherein thetotal weight of the ocular implant is between about 100 μg and about 2mg.
 4. The ocular implant of claim 1, wherein the implant is 60% byweight the active agent and 40% by weight the carrier.
 5. The ocularimplant of claim 1, wherein the implant is suitable for intravitrealimplantation.
 6. The ocular implant of claim 1, wherein the ocularcondition is elevated intraocular pressure (IOP).
 7. The ocular implantof claim 1, wherein the ocular condition is uveitis.
 8. The ocularimplant of claim 1, wherein the ocular condition is maculardegeneration.